Logo of edrvArchiveHomepageTES HomepageSubscriptionsSubmissionAbout
Endocr Rev. Jun 2010; 31(3): 343–363.
Published online Feb 17, 2010. doi:  10.1210/er.2009-0035
PMCID: PMC3365844

The Role of Blood Vessels, Endothelial Cells, and Vascular Pericytes in Insulin Secretion and Peripheral Insulin Action


The pathogenesis of type 2 diabetes is intimately intertwined with the vasculature. Insulin must efficiently enter the bloodstream from pancreatic β-cells, circulate throughout the body, and efficiently exit the bloodstream to reach target tissues and mediate its effects. Defects in the vasculature of pancreatic islets can lead to diabetic phenotypes. Similarly, insulin resistance is accompanied by defects in the vasculature of skeletal muscle, which ultimately reduce the ability of insulin and nutrients to reach myocytes. An underappreciated participant in these processes is the vascular pericyte. Pericytes, the smooth muscle-like cells lining the outsides of blood vessels throughout the body, have not been directly implicated in insulin secretion or peripheral insulin delivery. Here, we review the role of the vasculature in insulin secretion, islet function, and peripheral insulin delivery, and highlight a potential role for the vascular pericyte in these processes.


Insulin transport from the bloodstream to its target cells requires transport across a vascular endothelial barrier. This step is regulated by many factors, including pericytes. Similarly, insulin transport from β-cells to the bloodstream requires efficient access to the vasculature. We review the role of the vasculature in insulin action and insulin secretion.

  • I. Introduction
  • II. Endothelial Cells and the Heterogeneity of Vascular Beds
  • III. Islet Vasculature and Insulin Secretion
    • A. Introduction to islet vasculature
    • B. The importance of the vasculature for pancreas development
    • C. Proper vascularization is also required for mature islet function
    • D. The role of islet revascularization during islet transplantation
  • IV. Peripheral Vasculature and Insulin Delivery
    • A. Introduction to peripheral vasculature and insulin delivery
    • B. Transendothelial transport of insulin
    • C. Effects of insulin on blood flow
    • D. Insulin-induced capillary recruitment
    • E. Molecular mechanism of capillary recruitment
    • F. Insulin resistance and muscle vasculature
    • G. Exercise-induced vascular changes
  • V. Vascular Pericytes: More Than Inert Contractile Cells
    • A. Introduction to pericytes
    • B. Platelet-derived growth factor-B: a key mediator of pericyte function
    • C. Diabetic complications: a key role for pericytes
    • D. Are pericytes multipotent progenitor cells?
    • E. Pericytes in normal islet function
    • F. Pericytes in islet tumors
    • G. A role for PDGF-B signaling in glucose uptake?
    • H. Inhibition of PDGFRβ and diabetes therapy
    • I. A role for pericytes in insulin-induced hemodynamic changes
  • VI. Summary/Conclusions

I. Introduction

Type 2 diabetes is a growing world epidemic (1,2). There appear to be two key steps in the development of type 2 diabetes: 1) the development of insulin resistance; and 2) β-cell decompensation. Although both of these processes are beginning to be understood at the molecular level, much remains to be elucidated. An important recent development is the discovery of the role that blood vessels play in the pathogenesis of these two conditions. The focus of this review is an investigation of the role that blood vessels and their constituent endothelial cells, vascular smooth muscle cells (vSMCs), and pericytes play in β-cell function and the development of insulin resistance. Several excellent reviews have described several of these topics (3,4), but this review will have a broader focus including both the role of blood vessels in islet development and function and introducing the pericyte as a novel mediator of these effects.

II. Endothelial Cells and the Heterogeneity of Vascular Beds

Blood vessels in the vascular beds of different tissues exhibit large structural variability, especially in the number of fenestrae and caveolae (5,6,7,8). Fenestrae are the approximately 100-nm pores covered by a permeable diaphragm resulting from the fusion of apical and basolateral plasma membranes. Caveolae are the 60- to 80-nm plasma membrane pits thought to be involved in endocytosis and transcytosis. For example, the highly permeable liver endothelium is termed “discontinuous” and contains larger than normal fenestrae that lack diaphragms (5). Liver endothelium also has many intercellular gaps that allow for easy access of blood-borne molecules to hepatocytes (5). In contrast, the nonfenestrated, caveolae-free endothelium of the brain vasculature contains many tight junctions and has very low permeability (5). This helps to form the blood-brain barrier, which regulates the entry of blood-borne molecules into the brain and preserves ionic homeostasis (9). The permeability characteristics of pancreatic islet and muscle vasculature lie somewhere between these two extremes. Islet vasculature is relatively permeable, and although it does not have gaps between endothelial cells, the endothelial cells are highly fenestrated to allow for facile nutrient sampling from blood, enabling islets to respond quickly to fluctuations in blood glucose and adjust insulin secretion as needed (10,11). In contrast, both cardiac and skeletal muscle vasculature are relatively impermeable to blood-borne macromolecules (5,6,12).

Endothelial cells form the inner lining of blood vessels. They are critically involved in many physiological functions, including control of vasomotor tone, blood cell trafficking, hemostatic balance, permeability, proliferation, survival, and immunity (5). However, endothelial cells are not the only component of blood vessels. Pericytes and vSMCs line the outer walls of blood vessels and play critical roles in blood vessel and endothelial cell function. Interestingly, despite the recent interest in the role of blood vessels in insulin secretion and insulin action, a role for pericytes in these processes has not been well described.

III. Islet Vasculature and Insulin Secretion

A. Introduction to islet vasculature

A complete understanding of the role of the vasculature in islet function requires an understanding of islet vascular architecture. Pancreatic islets are highly vascularized by a dense network of capillaries. The islet capillary network is approximately five times denser in islets than in the surrounding exocrine tissue (11). Although pancreatic islets account for approximately 1% of total pancreatic mass, they receive approximately 7–10% of total pancreatic blood flow (13). Traditionally, blood has been thought to flow from one to three arterioles into the intraislet capillary network and empty into venules in the islet periphery (14). However, real-time fluorescent tracing of blood flow patterns in mouse islets demonstrates that in the majority of cases, islets exhibit an inner-to-outer flow pattern where capillaries perfuse β-cells before other islet cell types and larger vessels exhibit an efferent rather than afferent flow pattern (15). β-Cells are intimately associated with islet endothelial cells and are usually no more than one cell distant from the bloodstream (16). Islet capillaries are highly fenestrated (10,11); in fact, they contain about 10 times more fenestrae than the surrounding exocrine tissue (8,11). This presumably allows for delivery of nutrients and growth factors into islets and enables efficient sampling of the blood to allow for rapid glucose-sensing.

Islet blood flow can be regulated by a number of metabolic and nonmetabolic factors. For instance, glucose almost doubles islet blood flow (17). Insulin decreases islet blood flow, likely due to resultant hypoglycemia, rather than a direct effect of hyperinsulinemia (18). ATP signals through islet A1 adenosine receptors to increase islet blood flow (19). This is in agreement with the effects of glucose on islet blood flow and suggests that increased islet cell metabolism promotes increased islet blood flow. Other nutrients and hormones have indirect effects on islet blood flow by interacting with vasodilators and vasoconstrictors (20,21). Finally, the central nervous system impacts islet perfusion; brain stem-dead donors have impaired islet hormone secretion (22). These studies demonstrate that islet blood flow is carefully controlled by various nutrients and growth factors and is exquisitely intertwined with the metabolic state of the organism.

B. The importance of the vasculature for pancreas development

A close relationship between islet endocrine cells and endothelial cells has been described, from early islet development through mature islet function. In the developing embryo, the pancreatic endoderm is located immediately beside the dorsal aorta, and the presence of the dorsal aorta is required for pancreatic differentiation and insulin expression (23). Overexpression of vascular endothelial growth factor-A (Vegf-a) in the developing pancreas under control of the pancreatic and duodenal homeobox 1 (PDX1) promoter leads to a hypervascularized pancreas with a 3-fold increase in islet number and islet area as well as ectopic insulin expression in the developing gut, suggesting that the vasculature is not only critical for initiation of pancreas development but also remains important for islet growth throughout maturity (23). The transcription factor PTF1A was identified as a crucial signal that is induced by signals from aortic endothelial cells and promotes the budding of the PDX1-positive pancreatic endoderm as well as insulin and glucagon expression (24).

Subsequent to the early requirement for pancreatic budding, endothelial cells, both directly and indirectly through sphingosine-1-phosphate, promote growth and budding of the dorsal pancreatic endoderm by induction of mesenchymal cell proliferation (25,26). This close relationship between islet endothelial cells and endocrine cells continues during the period of postnatal islet expansion. During the pronounced expansion of islet endocrine cells 1 wk after birth, there is an even more pronounced expansion of islet endothelial cells, leading to a marked increase in intraislet vascular density (27). Overexpression of VEGF-A by a tetracycline-inducible pancreas-specific bitransgenic system demonstrates increased islet endothelial cell formation. However, this actually causes reduced postnatal β-cell mass, suggesting that islet angiogenic signals must be maintained within narrow limits (28). These data indicate that endothelial cues are critically important for initiation of pancreatic budding and that endothelial cells remain vitally important for pancreas and islet growth throughout later embryonic and early postnatal development.

C. Proper vascularization is also required for mature islet function

The close relationship between islet endocrine cells and endothelial cells is important not only for pancreas development, but also for mature islet function. Knockout of VEGF-A by Pdx1-promoter-driven Cre recombinase leads to severely reduced islet vascular density, resulting in glucose intolerance (29). Interestingly, these mice display loss of endothelial fenestrae and increased numbers of endothelial caveolae, suggesting that caveolae attempt to compensate for the loss of secretory capacity that is brought about by the “tightening” of the remaining blood vessels (29). It is somewhat surprising that these mice do not display more severe glucose homeostasis defects given the severe reduction of islet vasculature. Additionally, no loss of islet cell area was noted despite the evidence linking endothelial cell cues to islet proliferation, as described above in Section III. B.

Several studies directly examined the role of VEGF-A in adult β-cell function. Because Pdx1 is expressed at high levels throughout the developing pancreas and at lower levels in adult β-cells, these studies used rat insulin promoter (RIP)-driven CRE to conditionally knock out VEGF-A specifically in β-cells. Similar to the PDX1-CRE knockout mice, the RIP-Cre VEGF-A knockouts displayed impaired glucose tolerance and defective in vivo insulin secretion (30,31). A role for VEGF-A in the adult islet has also been directly tested: tamoxifen-inducible PDX-1-CRE VEGF-A knockouts show glucose intolerance and reduced vessel density, although the effects of VEGF-A loss are less severe than when VEGF-A is absent from the beginning of pancreatic development (32). These studies suggest that loss of islet endothelial cells can negatively affect insulin secretion and contribute to glucose intolerance.

Not surprisingly, loss of islet endothelial cells has a more severe effect in obese animals. RIP-CRE-mediated deletion of VEGF-A in high-fat diet-fed animals leads to more severe glucose intolerance and reduction in insulin secretion than in lean knockouts (33). Interestingly, these high-fat diet-fed mice are able to normally expand their β-cell mass, suggesting that normal islet endothelial cell density is dispensable for compensatory islet hyperplasia in response to obesity. Two potential explanations for the preserved ability of these mice to expand their β-cell mass could be residual VEGF-A due to inefficiency of the Cre promoter, which can vary with the distance between loxP sites (34), or the presence of other VEGF isoforms in islets (35). Because Cre is usually not expressed in 100% of its target cells, the remaining cells could produce enough VEGF-A to explain the continued presence of some islet endothelial cells. These remaining endothelial cells could be sufficient to promote β-cell mass expansion.

In addition to VEGF-A, several other islet proteins have been demonstrated to play a role in adult islet vascularization and function. Fyn-related kinase, when overexpressed under control of the RIP, causes reduced in vivo insulin secretion and mild glucose intolerance, which appears to be due to reduced islet blood flow and abnormal capillary morphology (36). Similarly, β-cell or pancreas-specific deletion of von Hippel-Lindau factor, the protein that controls the degradation of hypoxia-inducible factor-1α (HIF-1α), leads to glucose intolerance and impaired insulin secretion, which is mediated through an increase in Hif-1α expression (37). This study demonstrates that a direct effect of vessel loss (i.e., increased hypoxia) is able to mediate the same effect as actual vessel loss. This might seem somewhat paradoxical, because HIF-1α directly up-regulates Vegf-a expression and thus would be expected to increase islet vascularization (38). However, HIF-1α also directly alters the expression of genes involved in β-cell function in these mice, reducing the capacity of β-cells to mediate glucose uptake, glucose metabolism, and insulin secretion (37). Conversely, mice in which the antiangiogenic factor thrombospondin-1 is knocked out have enlarged hypervascular islets (39). Taken together, these data suggest that decreased islet vascularization or blood flow can have a deleterious effect on islet insulin secretion and whole-body glucose tolerance. Conversely, increased islet vascularization has the opposite effect.

In addition to the data gleaned from various knockout mice, several animal models of diabetes suggest a close relationship between islet vascularization and insulin secretion. For example, in Zucker fatty (ZF) and Zucker diabetic fatty rats, islets become more vascularized during the obesity-induced expansion of islet mass (40). Interestingly, as diabetes and loss of β-cell mass ensue in the Zucker diabetic fatty rats, islet vasculature decreases (40). A similar association between loss of islet capillary density and progression of diabetes is observed in the Otsuka-Long-Evans-Tokushima fatty rat model (41). These data provide further evidence that islet mass and the amount of islet vasculature are critically linked. Similarly, islet blood flow and blood pressure are elevated in nonobese diabetic GK rats, obese Zucker rats, obese Wistar rats, and GK-Wistar F1 hybrid rats (42,43,44). Islet blood flow is similarly increased in 1-month-old ob/ob vs. lean B6 mice during a period of hyperglycemia, hyperinsulinemia, and β-cell expansion (45). Islet blood flow was normalized in 6- to 7-month-old ob/ob mice, suggesting that increased islet blood flow is important during expansion of β-cell mass in response to hyperglycemia. A number of islet capillary changes were noted in adult db/db mice, including loss of islet capillaries, increased capillary diameter, and pericyte hypertrophy (46). Together, these data suggest that an increase in islet vascularization and blood flow accompanies compensatory β-cell mass expansion in response to hyperglycemia. When β-cells are no longer able to expand and decompensation occurs, loss of islet vasculature also occurs. Interestingly, insulin-deficient mice have more islet capillaries and bigger islets (47), which could indicate that insulin inhibits islet vascularization. Alternatively, this effect may be a compensatory response whereby islet vasculature and islet size increase in response to insufficient levels of insulin secretion.

Islet endothelial cells have recently been shown to play a critical role in producing islet basement membrane. β-Cells appear incapable of forming their own basement membrane (48), and deletion of VEGF-A under the Pdx1 promoter results in a loss of islet, but not acinar tissue basement membrane (49). Vascular endothelium-produced laminin-411 and laminin-511 appear to be critical for insulin gene expression and β-cell proliferation in a β1-integrin-dependent manner (49). Similarly, treatment of islets with endothelium-conditioned culture medium increases glucose-stimulated insulin secretion and islet insulin content, an effect that is blocked by addition of a neutralizing antibody to the β1-chain of laminin (50). Purified islet endothelial cells can also stimulate β-cell proliferation through secretion of hepatocyte growth factor (51). These results might shed some light on the described link between islet hyperplasia and increased islet vascularization. Hyperglycemia could trigger VEGF-A secretion from islet endocrine cells. This in turn stimulates vessel growth, basement membrane production, and hepatocyte growth factor production and secretion, which ultimately leads to increased insulin production and β-cell proliferation. Some caution is necessary in applying these findings to human islets, however, because it was recently demonstrated that blood vessels in human islets are surrounded by a unique double basement membrane (52).

D. The role of islet revascularization during islet transplantation

One area in which the process of islet vascularization is thought to be especially important is during islet transplantation. The success of islet transplantation can critically hinge on the ability of transplanted islets to establish functional vasculature (53,54). In addition to immunorejection of newly transplanted islets, islet survival has proved a major challenge to the success of this procedure (55). Isolation of islets for transplantation damages islet endothelial cells and obviously involves the severing of native vasculature (56,57,58). Thus, newly transplanted islets must reestablish a functional vascular network, a process that is believed to involve angiogenesis and possibly vasculogenesis (57). Not surprisingly, newly transplanted islets are less vascularized immediately after transplant, and even after several weeks they remain less vascularized and maintain a lower oxygen tension than native pancreatic islets (59,60). Islet death and apoptosis are common problems after transplant, with islet cell apoptosis increasing and β-cell mass decreasing 1–3 d after transplant (61,62). Given the important connection between islet endocrine cells and islet endothelial cells described in Section III. C, it is not hard to imagine that lack of a functional vasculature might play a direct role in this increased islet death. Additionally, the resultant hypoxia and/or ischemia could also strongly contribute to increased islet apoptosis. In support of this, Hif-1α expression is increased in newly transplanted islets, and suppression of Hif-1α in transplanted islets reduces β-cell death (63). Once again, this might seem paradoxical, due to the ability of HIF-1α to increase Vegf-a expression (38), but HIF-1α also stimulates many other responses, including hypoxia-induced growth arrest and apoptosis, both of which would negatively impact the survival of transplanted islets (64).

Endothelial cells from the transplant recipient were originally thought to be the major contributor to posttransplantation vessel formation, but recent evidence suggests that donor endothelial cells also play an important role in islet revascularization. By using lacZ- or GFP-tagged donor endothelial cells, it has been demonstrated that after transplantation, islet vasculature is chimeric and is composed of host and donor endothelial cells, both of which contribute to functional blood vessels (65,66,67). These data suggest that factors that stimulate angiogenesis in isolated islets during culture and transplantation might have a positive impact on the success of the transplantation process.

Considerable effort is being devoted to discover the effects of proangiogenic factors on the success of revascularization and survival of newly transplanted islets. For example, Vegf-a overexpression in transplanted mouse islets has been shown to cause increased vascularization of and increased blood flow to newly transplanted islets, resulting in increased islet insulin content, improved recipient glucose tolerance, and increased β-cell survival (68,69,70). Similarly, overexpression of the proangiogenic growth factor angiopoeitin-1 (Ang-1), which is normally produced by islets (30), in transplanted islets leads to increased glucose tolerance, glucose-stimulated insulin secretion, islet vascular density, and islet survival (71). Interestingly, Ang-1 can stimulate pericyte migration to endothelial cells, so these studies may suggest a role for pericytes in newly transplanted islets and revascularization. Pericytes are well-described to influence endothelial cell maturation and proliferation, so proper pericyte coverage could be important in this regard. Conversely, blockade of the angiogenesis inhibitor thrombospondin-1 in transplanted islets leads to increased vascularization and improved glucose-stimulated insulin secretion (72). Prolactin overexpression in newly transplanted islets has similar beneficial effects on islet vascularization and functionality (73). Finally, coculture of human endothelial cells and mesenchymal stem cells (MSCs) with isolated islets increases islet angiogenesis and suggests a potential method for increasing vascularization of newly transplanted islets (74). Each of these studies demonstrates the utility of promoting efficient islet vascularization after transplantation and demonstrates beneficial effects on β-cell survival and function. Therefore, the elucidation of additional factors that are critical for islet vascularization may contribute greatly to the treatment of diabetes.

One fascinating new model for studying the revascularization of newly transplanted islets was recently described. Isolated islets were transplanted onto the retina of nude mice, and this procedure was able to efficiently normalize streptozotocin-induced hyperglycemia (75). In contrast to other sites of transplant, retinal islet transplant allows for real-time in vivo monitoring of islet revascularization and could provide a useful model system for future studies of islet vascularization during transplantation.

IV. Peripheral Vasculature and Insulin Delivery

A. Introduction to peripheral vasculature and insulin delivery

Insulin signaling in skeletal muscle is critical in glucose disposal, accounting for almost 90% of whole-body glucose disposal in humans (76). This is compared with adipose tissue, which is estimated to account for less than 1% of whole-body glucose disposal in humans and rodents (77,78). The role of the muscle vasculature is beginning to be appreciated as a factor that influences the myocyte’s response to insulin. Loss of skeletal muscle capillary density is observed in both insulin resistance and in type 2 diabetes, and insulin action is positively correlated with capillary density (79). In cultured myocytes, insulin activates insulin receptor and insulin receptor substrate (IRS) proteins and stimulates glucose uptake in a matter of minutes (80,81,82). This suggests that when insulin is present at the myocyte cell surface, it is able to act almost instantaneously. Although it is tempting to assume that insulin can act as swiftly in vivo, results from several groups suggest that this is not the case. Measurements of insulin in lymph, which is derived from interstitial fluid, suggest that lymph insulin concentrations are reduced for up to 3 h during an insulin infusion compared with plasma insulin levels (83). Additionally, muscle glucose utilization correlates much more strongly with lymph than with plasma insulin levels (83). These data suggest that there is a delay between the appearance of insulin in the bloodstream and its appearance in the muscle interstitium. As is the case in cultured myocytes, insulin acts very quickly upon appearance in the interstitium. In support of this latter statement, direct injection of insulin into the muscle interstitium triggers muscle glucose uptake within minutes and circumvents the delay associated with iv insulin delivery (84).

Recently, the delivery of insulin to myocytes has come under increased scrutiny for many of the reasons mentioned above. Wang et al. (85) demonstrated that after 10 min of fluorescein isothiocyanate (FITC)-insulin infusion, the majority of FITC-insulin in muscle is localized within endothelial cells, suggesting that insulin is rapidly transported from the bloodstream into endothelial cells. Interestingly, after 1 h, most FITC-insulin is still concentrated in muscle endothelial cells, suggesting that transport from endothelial cells to the muscle interstitium is a slow process (85). Several studies suggest that insulin is only degraded at low levels by endothelial cells and that muscle lymph flow is relatively slow compared with other tissues, suggesting that any clearance of insulin from the muscle interstitium is likely due to uptake by myocytes (86,87,88). These results suggest that the transendothelial transport of insulin is a rate-limiting step in muscle insulin action. In support of this conclusion, direct injection of insulin into muscle lymph causes very rapid insulin action, suggesting that direct injection sidesteps the rate-limiting step (84). Interestingly, although the interstitial passage of insulin does not appear to be a rate-limiting step under normal conditions, injection of insulin into lymph of ob/ob mice shows a delayed action as compared with lean mice, suggesting that the movement of insulin within the muscle interstitium might be impaired under conditions of insulin resistance (89).

The heterogeneity of the body’s vascular beds provides further support for a muscle-specific delay in insulin action. As mentioned above, the liver vasculature is highly permeable (5), and in fact, insulin-stimulated inhibition of hepatic glucose output occurs much more quickly than insulin-stimulated muscle glucose disposal (90). Although the more rapid effect of insulin on liver has not been directly linked to increased delivery of insulin, the higher permeability of liver vs. muscle blood vessels suggests that this is a likely cause. Interestingly, inhibition of hepatic glucose output occurs at even low levels of insulin infusion, suggesting that the highly permeable liver vasculature does not impede the transport of insulin as is the case in muscle (91). In support of this, the concentration of lymph insulin required to stimulate muscle glucose uptake is similar to the plasma insulin concentration required to inhibit hepatic glucose output (3,91).

B. Transendothelial transport of insulin

The mechanism for insulin transport across the endothelium is not clear. Several in vitro studies suggest that the endothelial uptake of insulin is mediated by the insulin receptor (86,92,93). However, the study of a transendothelial transport process in vitro is complicated by the use of cultured cells or the severing of native blood vessels. Therefore, the in vivo setting seems to be a more reliable place to study the vasculature. Indeed, in vivo results suggest that the transport of insulin across the endothelium does not appear to be saturable, even at pharmacological concentrations of insulin, suggesting that it is not a receptor-mediated process (94,95). At a minimum, these data seem to suggest that at least at high levels of insulin, transport can occur by a non-insulin receptor-mediated transcellular or paracellular process. In some respects, a paracellular transport process would be somewhat surprising given the tightness of muscle endothelium (5,6,12).

Recent research has focused on possible mechanisms for insulin transport across endothelial cells. In vitro studies in cultured endothelial cells support an insulin receptor-mediated pathway for insulin uptake because blockade of several insulin-signaling pathways inhibits this process (96). Confocal imaging studies suggest colocalization of FITC-insulin with the insulin receptor in muscle endothelial cells (85). These proteins also colocalize with caveolin-1, a protein involved in the formation of caveolae. Interestingly, caveolae are also increased in β-cell-specific VEGF-A knockouts, which display a dramatic loss of islet endothelial fenestrae, as mentioned in Section III. C. In this situation, caveolae are thought to mediate the transendothelial transport of insulin from β-cells to the bloodstream to compensate for the loss of endothelial cell fenestrae, so there is some precedent for caveolae-mediated transport of insulin across endothelial cells. Although the cellular colocalization of labeled insulin, insulin receptor, and caveloae is intriguing, further studies will be necessary to provide a conclusive link between transendothelial insulin transport in muscle and caveolae. Interestingly, transendothelial transport of insulin has been directly demonstrated by using 125I-labeled insulin in heart muscle (97).

C. Effects of insulin on blood flow

Insulin has been demonstrated to cause a number of direct effects on the vasculature. Although somewhat controversial, insulin appears to increase total blood flow within skeletal muscle. Baron (98) was the first to theorize that the ability of insulin to increase limb/muscle blood flow might be a critical part of its delivery and its ability to stimulate glucose uptake. Although this has been supported by a number of studies in both normal and obese or insulin-resistant situations (99,100,101,102,103,104,105,106,107,108,109,110,111), there are also a number of studies that failed to show an insulin-induced increase in blood flow, especially at physiological levels of insulin (112,113,114,115,116,117,118,119). This has led to some disagreement in the field as to whether insulin can increase blood flow at physiological levels (120,121). There are a number of theories to explain why an insulin-stimulated increase in blood flow is not always observed. Barrett et al. (3) argue that pharmacological doses of insulin clearly act to increase limb blood flow, but the necessity for large doses of insulin and the long durations required to observe an effect cast doubt on the normal physiological relevance of this effect. Clark (4) and Barrett et al. (3) both suggest that although there is not always an observed increase in total blood flow, insulin can influence which vessels in muscle are perfused without changing total blood flow. Specifically, this switch involves the ability of insulin to increase vasomotion, the relaxation of terminal arterioles, and shift blood flow from a nonnutritive pathway, i.e., one that has little or no exchange with the interstitial fluid surrounding the muscle fibers, to a nutritive pathway, i.e., one where blood flows through capillaries that allow for nutrient exchange with the muscle interstitium that is underperfused in the basal state (4). This insulin-induced shift provides a greater surface area for nutrient exchange and may be the primary vascular effect caused by insulin (4).

D. Insulin-induced capillary recruitment

The ability of insulin to stimulate relaxation of terminal arteries and promote flow through the nutritive pathway is termed capillary or microvascular recruitment and, in contrast to insulin-induced effects on total blood flow, seems to be gaining general acceptance (3,4). In normal muscle tissue, only about two thirds of the vasculature is normally perfused with erythrocytes at any given time (122), although other studies have demonstrated by live imaging that nearly all capillaries in the spinotrapezius muscle and diaphragm are perfused at rest (123). Potentially, differences in flow rates and the extent of perfusion between different muscle capillary beds could explain this apparent inconsistency. By shifting blood flow from nonnutritive vessels to nutritive capillaries, insulin is able to increase the available surface area for nutrient exchange and theoretically increase the surface area for its own delivery and that of glucose to myocytes (3) (Fig. 11,, A and B; and a color version in Supplemental Fig. 1, published as supplemental data on The Endocrine Society’s Journals Online web site at http://edrv.endojournals.org).

Figure 1
Transendothelial transport of insulin and glucose to muscle interstitium. A, In the normal state, insulin and glucose must travel from the blood stream across endothelial cells and potentially pericytes to reach the muscle interstitium and activate insulin ...

Two notable experimental advances greatly aided the elucidation of insulin’s ability to promote capillary recruitment: 1-methylxanthine (1-MX) metabolism (124), and contrast-enhanced ultrasound (CEU) (125). In short, 1-MX is a substrate for the endothelial cell enzyme xanthine oxidase, which is found only in smaller arterioles and capillaries and catalyzes the conversion of 1-MX to 1-methylurate (124). Disappearance of 1-MX from blood suggests an increase in available endothelial cell area that allows for 1-MX entry (124). Insulin administration significantly increases 1-MX metabolism, suggesting a dilation-mediated increase in endothelial cell area (124). CEU uses gas-filled microbubbles as a contrast agent and a surrogate for erythrocytes to measure blood flow and has demonstrated insulin-induced increases of muscle capillary volume without changes in total blood flow (125). Importantly, both 1-MX metabolism and CEU have demonstrated the ability of physiological levels of insulin to induce capillary recruitment (124,125,126,127). Insulin-induced capillary recruitment has also been investigated in skin, which has the advantage of being much easier to access and monitor (3,4,128). These results are generally consistent with those in muscle and have been reviewed in detail elsewhere (3,4).

E. Molecular mechanism of capillary recruitment

Insulin stimulates its vasodilatory actions associated with capillary recruitment through up-regulation of endothelial nitric oxide synthase (eNOS) in muscle endothelial cells (129,130,131,132) (Fig. 2A2A,, and a color version in Supplemental Fig. 2). eNOS production is induced by insulin receptor activation of the phosphatidylinositol-3-kinase (PI3K) signaling cascade, which ultimately increases eNOS expression and subsequent nitric oxide (NO) production for vasodilation (129,131,132,133). Somewhat paradoxically, insulin can also stimulate vasoconstriction by activating endothelin via the ERK 1/2 pathway (131,134) (Fig. 2B2B).). Therefore, it seems that in the normal case, vessel relaxation and constriction are tightly controlled by an organism’s metabolic state, and this suggests that perturbations to this balance might affect delivery of nutrients and insulin itself to myocytes. Indeed, vessels from obese ZF rats display reduced levels of eNOS protein compared with lean rats, and insulin treatment stimulates only vasoconstriction, which presumably contributes to the development of insulin resistance (135). Similarly, blockade of endothelin-1 receptors in obese humans results in significant vasodilation, but a similar effect is not seen in lean humans (136). A shift toward insulin-induced vasoconstriction is also observed by pharmacologically inhibiting eNOS with NO inhibitors, confirming the NO independence of this vasoconstriction (134,135). As might be predicted, eNOS knockout mice display insulin resistance (137). These data suggest that under conditions of insulin resistance, the balance of insulin action shifts toward vasoconstriction. This further exacerbates insulin resistance by reducing the access of insulin and nutrients to myocytes by decreasing nutritive flow and available capillary surface area.

Figure 2
Insulin-induced vasodilation and vasoconstriction signaling in endothelial cells and pericytes. A, Insulin signaling in endothelial cells results in increased NO production and secretion, which stimulates the dephosphorylation of myosin in pericytes and ...

F. Insulin resistance and muscle vasculature

As is the case in pancreatic islets, muscle vascular defects worsen with insulin resistance and type 2 diabetes. Numerous studies demonstrate that the insulin-induced increase in capillary recruitment is blunted in cases of insulin resistance and obesity (Fig. 1C1C).). For example, insulin-resistant ZF rats show reduced capillary recruitment (138). Similarly, insulin resistance induced by various agents such as TNF-α, intralipid/heparin, glucosamine, or α-methylserotonin also reduces capillary recruitment (139,140,141,142). Importantly, the extent of muscle capillary recruitment is positively correlated with glucose uptake (140,141), suggesting a possible causal relationship between these two processes. Human type 2 diabetic patients demonstrate a reduced muscle capillary permeability-surface area in response to hyperinsulinemia, suggesting a defect in insulin-induced capillary recruitment (143). A likely mechanism for these observations, as mentioned in Section IV. E, is the insulin resistance-induced decrease of eNOS activation, which leads to reduced vasodilation. These data suggest that muscle vascular dysfunction accompanies insulin resistance.

Whether insulin resistance causes vascular dysfunction or vice versa is not entirely clear. Evidence suggests that muscle vascular defects are among the earliest phenotypes observed as insulin resistance progresses and that diminished NO production and increased vasoconstriction precede the development of type 2 diabetes (144). Due to the importance of insulin signaling in capillary recruitment, it would not be surprising if reduced eNOS activation was mediated by the same mechanism as desensitization of myocyte insulin signaling. Insulin resistance in myocytes has been demonstrated to occur downstream of insulin receptor binding, likely at the level of the IRS proteins (145,146). One can imagine that the same desensitization of insulin signaling could blunt the PI3K pathway in endothelial cells and subsequent eNOS activation, thus leading to reduced vascular dilation. The subsequent reduction in available capillary surface area would likely reduce transendothelial insulin transport to myocytes and further blunt myocyte insulin signaling, continuing a vicious cycle. As the potential involvement of the insulin receptor in transendothelial transport is further elucidated, defects in this process might also become important for the development of insulin resistance.

Several animal models are informative regarding the effects of insulin on muscle vasculature. Prominent among these models are the vascular endothelial cell insulin receptor knockout (VENIRKO) mice, which somewhat surprisingly, are not insulin resistant (147). An initial reaction to this result might be that insulin-mediated vasodilation is not a critical process for muscle glucose disposal. This suggests that insulin delivery to the periphery is possible without the endothelial cell insulin receptor under normal circumstances. However, both eNOS and endothelin-1 mRNA levels are reduced in the VENIRKO mice (147), suggesting that the lack of insulin resistance in these mice may not be surprising because the signals for both vasoconstriction and vasodilation are reduced, resulting in no net changes in vasomotion. When considering these results, it is important to note that in lean mice, creating insulin resistance has historically been somewhat complicated because even muscle-specific knockout of the insulin receptor (MIRKO mice), one of the most critical proteins involved in muscle insulin signaling, results in normal glucose tolerance and insulin sensitivity (148). Finally, the insulin-like growth factor-1 receptor, which is found at high levels in muscle endothelial cells (149), could also compensate for loss of the insulin receptor. Additionally, as mentioned in Section IV. E, eNOS knockout mice are also insulin resistant (137). No studies linking knockout of endothelin-1 to amelioration of insulin resistance have been reported, but this result might be predicted.

G. Exercise-induced vascular changes

Exercise has been demonstrated to promote many of the same changes in the muscle vasculature as insulin (150). Exercise efficiently increases muscle capillary recruitment, as well as total muscle blood flow (151). Interestingly, the mechanism for insulin- and exercise-induced increases in muscle perfusion appear distinct because the exercise mechanism is NO-independent (152). Exercise-induced vascular changes are not blunted by insulin resistance or obesity (153). These data suggest that even in cases of prolonged disease progression, exercise might be able to remedy some of the effects of insulin resistance on the muscle vasculature.

V. Vascular Pericytes: More Than Inert Contractile Cells

A. Introduction to pericytes

Although pericytes were first described almost 150 yr ago, they are still not entirely understood. Charles Rouget was the first to identify pericytes in 1873 when he described a population of perivascular cells that he regarded as contractile elements (154). In 1923, Zimmermann named these cells “Rouget cells” after their discoverer, or “pericytes” because of their location in proximity to endothelial cells (peri, around; cyte, cell) (155). Together, pericytes and the related vSMCs make up a class of cells, termed mural cells, which provide support to blood vessels of all sizes (156). By convention, the mural cells associated with larger vessels such as arteries and veins are called vSMCs, whereas those associated with smaller vessels, such as capillaries, arterioles, and venules, are termed pericytes (157). vSMCs are highly contractile, typically express high levels of α-smooth muscle actin (α-SMA), and can form multiple concentric layers around blood vessels (156). Additionally, vSMCs have their own basement membrane, which is rich in elastin and fibrillar collagen and is separate from the vascular basement membrane (156,158). Pericytes, on the other hand, typically form a single discontinuous layer around smaller vessels (157). They are intimately associated with endothelial cells and reside in a shared basement membrane that is produced by both pericytes and endothelial cells (159). Pericytes typically express high levels of cell-surface chondroitin sulfate proteoglycan neuron-glial 2 (NG-2), which is commonly used as a histological pericyte marker (155).

Pericyte coverage and morphology can vary between different vascular beds. Pericytes in certain tissues have acquired specialized names, such as Ito cells in liver (named after their discoverer, Toshio Ito) and mesangial cells in the kidney glomerulus (155,160). The highest level of pericyte coverage is seen in the central nervous system, where pericytes are thought to play an important role in the formation and maintenance of the blood-brain barrier (161,162).

Although pericytes were originally thought to be solely involved in contractile processes, they have recently been shown to have many additional functions. Pericytes, like vSMCs, can indeed mediate vessel contraction and influence vascular diameter and capillary blood flow (163). Loss of pericytes leads to excessive endothelial membrane folding and luminal cytoplasmic protrusions, which likely impacts vessel perfusion and possibly nutrient exchange (164). Pericytes can communicate with endothelial cells through a variety of signaling pathways, and they promote endothelial cell differentiation and maturation (165). Pericytes are also thought to limit endothelial cell proliferation; thus, loss of pericytes can lead to endothelial cell hyperplasia (164). Pericytes also play a critical role in angiogenesis, because they are typically found near the tips of sprouting vessels and where they are thought to guide the sprouting processes by expressing VEGF (166,167,168,169,170).

B. Platelet-derived growth factor-B: a key mediator of pericyte function

Platelet-derived growth factor B (PDGF-B) and its receptor, PDGF receptor-β (PDGFRβ), are critically involved in pericyte recruitment and proliferation (157). PDGF-B belongs to the PDGF family of proteins, which shares structural homology with the VEGF protein family (171,172). In addition to PDGF-B, there are three other mammalian PDGF family members, PDGF-A, PDGF-C, and PDGF-D (172). PDGF was originally identified as a constituent of whole blood that was absent in cell-free plasma (173,174,175) and was later purified from human platelets (176,177,178,179). The PDGF family members function as homo- and heterodimers (180). PDGF-B is normally expressed in vascular endothelial cells, megakaryocytes, and neurons, whereas PDGF-A and PDGF-C are highly expressed in epithelial cells, muscle, and neuronal progenitor cells (172).

There are two PDGF receptors, PDGFRα and PDGFRβ. Ligand binding causes homo- or heterodimerization of PDGFRs, which activates their cytoplasmic tyrosine kinase domains and results in autophosphorylation of several tyrosine residues in their cytoplasmic tails (181). The phospho-tyrosine residues create docking sites for a variety of adaptor proteins, leading to activation of a wide variety of signaling pathways, including the RAS-MAPK, JNK/SAPK, PI3K/AKT, and protein kinase C (PKC) pathways (182,183). Interestingly, PDGFR signaling through different pathways appears to be additive rather than producing distinct outcomes. In a tour de force study, Tallquist et al. (184) created an allelic series of tyrosine to phenylalanine mutations, which resulted in blunted but qualitatively similar developmental effects. Ligand occupancy promotes internalization and subsequent lysosomal degradation of PDGFR complexes, limiting the duration of signaling (185,186,187).

PDGFRα binds both PDGF-A and PDGF-B with high affinity, whereas PDGFRβ binds only PDGF-B with high affinity (180). However, the receptor complex thought to mediate in vivo PDGF-B signaling is the PDGFRβ homodimer (157,158,172). In addition, outside of human platelets, the expression patterns of PDGF-A and PDGF-B are generally nonoverlapping, suggesting that the PDGF-AB heterodimer, which can bind to both PDGFRs, might have limited in vivo significance (180,183).

PDGF-A and PDGF-B are the best described PDGF ligands. Although PDGF-A is involved in a variety of diverse developmental and organogenesis processes (172), the major function of PDGF-B is its role in stimulating the migration of pericytes and vSMCs to growing blood vessels (172). PDGF-B is secreted as a homodimer from endothelial cells, where it is retained on the cell surface by a C-terminal heparan-sulfate proteoglycan-binding retention motif (188,189). PDGFRβ on the surface of pericytes and vSMCs binds to PDGF-B, thus recruiting mural cells to the endothelial cell wall. Loss of the retention motif leads to decreased retention of PDGF-B on the cell surface (188,189,190). Lindblom et al. (191) have generated and characterized mice in which the PDGF-B retention motif has been deleted by targeted mutagenesis, causing a reduction in PDGF-B signaling. These mice display a loss of pericyte density, pericyte detachment, and abnormal capillary morphology in the developing brain, kidney, and retina, as well as the postnatal kidney and retina (191). PDGF-B and PDGFRβ knockout mice display similar, but more severe defects: a drastic loss of pericytes, widespread vascular leakage, general heart defects, and perinatal lethality (164,192,193,194,195).

Although PDGF-B and PDGFRβ are critically important for pericyte recruitment, the presence of pericytes in some organs of PDGF-B/PDGFRβ knockouts suggests that other factors are also important for pericyte biology. Notably, TGF-β is an important mediator of vSMC/pericyte differentiation (196,197). Additionally, Ang-1 and its receptor, endothelium-specific receptor tyrosine kinase-2, are important for signaling from pericytes/vSMCs to endothelial cells and play a role in pericyte recruitment (157).

Although the importance of PDGF-B signaling and pericyte coverage in the microvasculature has been well described, little has been reported regarding any influence pericytes might have on insulin secretion and peripheral insulin action. Pericytes are found at relatively high densities in skeletal and cardiac muscle (198,199) and in pancreatic islets (200). PDGF-B signaling can promote β-cell proliferation in vitro, but only under conditions of PDGFRβ ectopic overexpression; endogenous PDGFRβ expression in β-cells is quite low (201). Therefore, PDGF-B does not directly signal to β-cells.

C. Diabetic complications: a key role for pericytes

Pericytes play a central role in diabetic complications. Loss of pericytes is one of the first observable changes in diabetic retinopathy and is ultimately followed by increased vascular permeability (202). Interestingly, Geraldes et al. (203) recently demonstrated that glucose increases the expression of PKC-δ, which results in down-regulation of PDGFRβ/AKT survival signals and pericyte death. The vasculature also plays a clear role in the progression of nephropathy (204). Knockout of PDGF-B/PDGFRβ or loss of PDGF-B retention results in defects in the pericyte-like mesangial cells, leading to defective glomerulogenesis, glomerulosclerosis (191,194,195), and proteinurea (191), a hallmark of diabetic nephropathy. Diabetic neuropathy is characterized by reduced blood flow, capillary basement membrane thickening, and pericyte degeneration (205). Tilton et al. (206) used transmission electron microscopy to study pericyte morphology and density in a variety of skeletal muscles from nondiabetic and diabetic humans. Similar to what is observed in diabetic retinopathy, they noted an increased degeneration of pericytes in the type 2 diabetic muscles. Pericyte changes are therefore associated with diabetes and are found in most of the microvascular complications associated with diabetes.

D. Are pericytes multipotent progenitor cells?

One exciting new field of pericytes involves their potential role as MSC-like progenitor cells. MSCs, also known as multipotent mesenchymal stromal cells, are undifferentiated, self-renewable cells that are present in bone marrow and mesenchymal tissues (207). Interest in MSCs in relation to diabetes intensified when it was reported that transplanted bone marrow MSCs initiated pancreas regeneration and improved diabetes in mice and humans (208,209,210). However, other studies did not demonstrate any evidence for transdifferentiation of bone marrow cells into β-cells (211,212), so this process could be dependent on the stage of diabetes progression and/or the isolation and transplantation techniques. Transplantation of purified MSCs was likewise able to normalize hyperglycemia and promote islet growth in streptozotocin-treated mice (213). Crisan et al. (214) recently demonstrated that pericytes isolated from human mesenchymal tissues, including skeletal muscle, pancreas, and adipose tissue, were able to serve as multilineage progenitor cells reminiscent of MSCs. Specifically, this study demonstrated that purified pericytes from any of these organs, when cultured in a tissue-specific growth medium, could differentiate into myocytes, adipocytes, osteocytes, and chondrocytes (214). Although pericytes isolated from pancreas were used as progenitor cells, the authors did not report on the ability of isolated pericytes to differentiate into β-cells or any other pancreatic cell type. This presents the intriguing question: can pericytes serve as β-cell progenitors? In vivo lineage-tracing experiments using a tetracycline-inducible CRE recombinase under the control of the adipogenic peroxisome proliferator-activated receptor-γ promoter to indelibly mark cells with β-galactosidase demonstrate that adipocyte progenitors are perivascular cells that express several pericyte markers, including NG-2, PDGFRβ, and α-SMA (215). One can imagine using a similar system with a β-cell-specific CRE recombinase such as Pdx1-CRE to determine whether islet pericytes can analogously serve as progenitors to β-cells.

E. Pericytes in normal islet function

The role of pericytes in normal islet function is not completely understood, but islet pericyte changes associated with a number of pathological conditions have been described. In obese animals, islet pericytes become more hypertrophied and assume vSMC characteristics (46). Notably, pericytes take on more of a smooth muscle cell-like appearance, and it has been speculated that this is potentially in response to increased islet blood pressure (46). We and others have similarly observed an increase in α-SMA and NG-2 staining densities in islets from ob/ob mice, consistent with obesity-induced pericyte hypertrophy (Ref. 216 and Supplemental Fig. 3). Similarly, hypertensive Ren2 rat islets have increased pericyte proliferation, migration, hypertrophy, and α-SMA staining (217). In rats overexpressing human islet amyloid polypeptide, there is a reduction in both β-cell mass and islet capillary density, along with increased pericyte apoptosis and loss (218). Finally, in a rat model of type 2 diabetes, the matrix between islets and the surrounding exocrine tissue widens, due to an increase in pericytes and inflammatory cells in this region (219). The authors of these studies noted evidence of pericyte differentiation into stellate cells, but the use of α-SMA as a stellate-cell marker seems somewhat questionable due to its well-described role as a vSMC marker (155).

F. Pericytes in islet tumors

The role of pericytes in islet-cell tumors has been intensively investigated (220,221,222,223,224,225,226,227). PDGFRs are expressed in tumor pericytes, and treatment with a drug that selectively inhibits PDGFRα and PDGFRβ blocks further growth of end-stage tumors by causing pericyte detachment and disrupting tumor vasculature (220). Pericyte loss induced by treatment with imatinib mesylate improves the efficacy of metronomic chemotherapy by rendering endothelial cells more sensitive to the actions of the cytotoxic drugs (224). Treatment with imatinib mesylate, metronomic chemotherapy, and a selective VEGFR inhibitor elicits regression of solid islet tumors and increases median survival (224). Some of the effects of PDGFRβ inhibition in islet tumors are mediated by elimination of PDGFRβ-positive perivascular progenitor cells, which can differentiate into mature pericytes (226). These data suggest that lack of pericytes improves drug delivery to tumor cells and might be beneficial for treatment.

Although the absence of tumor pericytes might be beneficial for drug delivery, it is also associated with increased tumor metastasis. β-Cell tumors that are deficient for neural cell adhesion molecule have leaky blood vessels with detached pericytes, which correlates with an increased incidence of metastasis (225). In agreement with this, PDGF-B retention-deficient mice with β-cell tumors exhibit increased metastasis, demonstrating a direct causal link between defective pericyte recruitment and increased metastasis (225). These findings directly translate to humans, because decreased α-SMA-positive pericyte coverage of tumor vessels correlates with increased metastasis and results in a poorer prognosis (228). Thus, although inhibition of PDGFR is an attractive option for improving tumor treatment, the benefits must be weighed against the increased metastatic potential associated with reduced tumor pericyte coverage.

G. A role for PDGF-B signaling in glucose uptake?

PDGFRβ has been investigated in relation to insulin signaling because it can activate several of the same signaling pathways as the insulin receptor. Specifically, the ability of PDGFRβ to activate AKT/PI3K signaling (183) has been investigated in relation to glucose uptake into myocytes and adipocytes. PDGF-B signaling can induce glucose transporter type 4 translocation in both cultured adipocytes (229) and mouse skeletal muscle (230). However, due to minimal endogenous expression of the receptor, this is only possible under conditions involving overexpression of PDGFRβ. These actions of PDGF-B are mediated independently of IRS-1 activation (229,230). Interestingly, exogenous overexpression of PDGFRβ in skeletal muscle has been used to demonstrate that defects in the insulin signaling pathway independent of IRS-1 can lead to insulin resistance (231). These data suggest that any effect of PDGF-B on insulin action is unlikely due to a direct effect of PDGF-B on parenchymal cells.

Although PDGF-B does not normally signal directly to myocytes, we have recently demonstrated that loss of PDGF-B activity does impact peripheral insulin sensitivity (200). In ob/ob mice, loss of PDGF-B retention causes decreased in vivo insulin secretion without a change in glucose tolerance (200). These mice have defective pericyte coverage in peripheral tissues involved in insulin action (200). Loss of pericytes can lead to increased vascular leakage (164,191,192,193,194,195), and indeed these mice display increased vascular permeability, especially in heart (200). Ultimately, this leads to increased transendothelial transport of insulin and increased whole-body insulin sensitivity (200). These data demonstrate an important and novel role for pericytes and PDGF-B in delivery of insulin to peripheral tissues.

H. Inhibition of PDGFRβ and diabetes therapy

One potentially interesting link between PDGF-B activity and diabetes concerns the effect of imatinib mesylate (Gleevec). Imatinib mesylate inhibits several receptor tyrosine kinases, including c-abl, c-kit, and PDGFRβ (232). Several studies have reported that imatinib mesylate lowers fasting blood glucose levels in diabetic patients treated for chronic myeloid leukemia (233,234,235). Another study reported no effect of imatinib mesylate treatment on glucose levels (236). However, Han et al. (237) recently demonstrated that treatment of db/db mice with imatinib mesylate drastically improves peripheral insulin sensitivity. The authors observed improved insulin sensitivity and decreased in vivo insulin secretion in response to a glucose challenge, but they attributed these effects to an amelioration of c-abl-induced endoplasmic reticulum stress in liver and adipose tissues. However, it is also possible that the observed increase in insulin sensitivity may also involve PDGFRβ inhibition. In accordance with this, treatment of mice with imatinib mesylate or a soluble form of PDGFRβ both prevents and reverses type 1 diabetes, whereas treatment with a c-kit inhibitor had little effect (238). None of these studies investigated the effect of imatinib mesylate treatment on pericyte coverage of islets or peripheral tissues, which could provide a potential mechanism for the improvement of diabetes. In support of this possibility, tumor-bearing mice treated with imatinib mesylate demonstrate a decrease in pericyte coverage and increased vessel leakiness, suggesting that a similar improvement of vascular permeability in peripheral tissues could improve insulin or nutrient delivery and possibly explain the effects of imatinib mesylate on diabetes (239). This suggests that further investigation into the effects of imatinib mesylate and other PDGFRβ inhibitors on diabetes treatment and pericyte coverage may be informative.

I. A role for pericytes in insulin-induced hemodynamic changes

In addition to the role for pericytes in insulin delivery to myocytes, pericytes and vSMCs also play an important role in insulin-induced capillary recruitment. NO produced by endothelial-expressed eNOS diffuses into vSMCs where it binds to and activates the heme moiety of guanylyl cyclase (240,241) (Fig. 2A2A).). This results in an increase of the local concentration of cGMP, which increases cGMP-dependent protein kinase G (PKG) signaling (240,241). This results in activation of myosin light-chain phosphatase and the opening of KATP channels (240). NO can also directly nitrosylate KATP channels, resulting in hyperpolarization of the vSMC plasma membrane and inhibition of calcium entry (240). Each of these NO-mediated effects results in vSMC relaxation and concomitant vasodilation. Conversely, endothelin-1 signals through its G protein-coupled receptors on the surface of vSMCs, ETA and ETB, to activate PKC signaling that results in increased calcium levels and vascular contraction (242,243,244) (Fig. 2B2B).). Interestingly, PKC signaling can be activated by lipid by-products like diacylglycerol and long-chain acyl-coenzyme A, which are increased in obesity (145) and can further promote vasoconstriction and exacerbate insulin resistance. Endothelin-1 and NO mediate their vasoconstriction and vasodilation effects on pericytes through similar mechanisms (163).

Modulation of vSMC or pericyte coverage and its effects on insulin-induced vascular constriction and dilation have not been directly studied, although one can imagine that loss of vSMCs or pericytes could reduce the ability of vessels to respond to insulin-induced changes in vascular tone. Additionally, loss of vSMCs/pericytes might lead to general increases in vessel dilation and muscle perfusion, resulting in increased capillary surface area and insulin/nutrient transport to muscle interstitium. Conversely, vSMC/pericyte hyperplasia might result in increased basal vascular contraction. Notably, vSMCs isolated from ZF rats showed reduced PKG activation by NO and cGMP, suggesting that insulin resistance also impedes this step in insulin-induced vasodilation (245). This defect was thought to be due to increased levels of superoxide anions because it was rescued by antioxidant treatment (245). In keeping with this, NO can be consumed by reactive oxygen species, resulting in the production of peroxynitrite (246). This suggests that increased metabolism and increased generation of metabolic by-products like reactive oxygen species could begin to explain a mechanism for defective eNOS/NO signaling in insulin-resistant animals and humans.

PDGF-B could play a direct role in controlling vascular dilation and constriction. Like insulin, PDGF-AB and to a lesser extent PDGF-A and PDGF-B increase eNOS expression (247). This suggests that, in addition to decreasing pericyte coverage, defects in PDGF signaling could directly contribute to the development of insulin resistance by reducing eNOS levels and increasing vasconstriction.

VI. Summary/Conclusions

Type 2 diabetes is a growing worldwide epidemic. The involvement of the vasculature in the processes of islet development, insulin secretion, and peripheral insulin action is undeniable. Although most recent research has focused on endothelial cells, the vascular pericyte is an intriguing candidate to play a role in these processes. From their involvement in diabetic complications to their function as mediators of insulin-induced vasodilation and vasoconstriction, the available information suggests a role for pericytes in the development of insulin resistance and type 2 diabetes. Future research will be critical to elucidate the role of the vascular pericyte in these processes.

Supplementary Material

Supplemental Data:


We are grateful to Robin Davies and Laura Vanderploeg for expert assistance in preparing Figs. 11 and 22.. We thank William Dove, Jon Odorico, Anath Shalev, and Xin Sun for critical review of the manuscript and helpful discussion.


This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK66369 and DK58037, National Institutes of Health Training Grant T32GN07215 (to O.C.R. and S.M.R.), and a Wisconsin Alumni Research Foundation fellowship (to O.C.R.).

Disclosure Summary: The authors have nothing to disclose.

First Published Online February 17, 2010

Abbreviations: Ang-1, Angiopoeitin-1; CEU, contrast-enhanced ultrasound; eNOS, endothelial NO synthase; FITC, fluorescein isothiocyanate; HIF-1α, hypoxia-inducible factor-1α; IRS, insulin receptor substrate; MSC, mesenchymal stem cell; 1-MX, 1-methylxanthine; NG-2, neuron-glial 2; NO, nitric oxide; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; Pdx-1, pancreatic and duodenal homeobox 1; PI3K, phosphatidylinositol-3-kinase; PKC, protein kinase C; PKG, protein kinase G; RIP, rat insulin promoter; α-SMA, α-smooth muscle actin; Vegf-A, vascular endothelial growth factor-A; vSMC, vascular smooth muscle cell; ZF, Zucker fatty (rats).


  • Mokdad AH, Bowman BA, Ford ES, Vinicor F, Marks JS, Koplan JP 2001 The continuing epidemics of obesity and diabetes in the United States. JAMA 286:1195–1200 [PubMed]
  • Diamond J 2003 The double puzzle of diabetes. Nature 423:599–602 [PubMed]
  • Barrett EJ, Eggleston EM, Inyard AC, Wang H, Li G, Chai W, Liu Z 2009 The vascular actions of insulin control its delivery to muscle and regulate the rate-limiting step in skeletal muscle insulin action. Diabetologia 52:752–764 [PMC free article] [PubMed]
  • Clark MG 2008 Impaired microvascular perfusion: a consequence of vascular dysfunction and a potential cause of insulin resistance in muscle. Am J Physiol Endocrinol Metab 295:E732–E750 [PMC free article] [PubMed]
  • Aird WC 2007 Phenotypic heterogeneity of the endothelium. I. Structure, function, and mechanisms. Circ Res 100:158–173 [PubMed]
  • Aird WC 2007 Phenotypic heterogeneity of the endothelium. II. Representative vascular beds. Circ Res 100:174–190 [PubMed]
  • Parton RG, Simons K 2007 The multiple faces of caveolae. Nat Rev Mol Cell Biol 8:185–194 [PubMed]
  • Zanone MM, Favaro E, Camussi G 2008 From endothelial to β-cells: insights into pancreatic islet microendothelium. Curr Diabetes Rev 4:1–9 [PubMed]
  • Stamatovic SM, Keep RF, Andjelkovic AV 2008 Brain endothelial cell-cell junctions: how to “open” the blood brain barrier. Curr Neuropharmacol 6:179–192 [PMC free article] [PubMed]
  • Bearer EL, Orci L 1985 Endothelial fenestral diaphragms: a quick-freeze, deep-etch study. J Cell Biol 100:418–428 [PMC free article] [PubMed]
  • Henderson JR, Moss MC 1985 A morphometric study of the endocrine and exocrine capillaries of the pancreas. Q J Exp Physiol 70:347–356 [PubMed]
  • Simionescu M, Gafencu A, Antohe F 2002 Transcytosis of plasma macromolecules in endothelial cells: a cell biological survey. Microsc Res Tech 57:269–288 [PubMed]
  • Jansson L, Carlsson PO 2002 Graft vascular function after transplantation of pancreatic islets. Diabetologia 45:749–763 [PubMed]
  • Bonner-Weir S, Orci L 1982 New perspectives on the microvasculature of the islets of Langerhans in the rat. Diabetes 31:883–889 [PubMed]
  • Nyman LR, Wells KS, Head WS, McCaughey M, Ford E, Brissova M, Piston DW, Powers AC 2008 Real-time, multidimensional in vivo imaging used to investigate blood flow in mouse pancreatic islets. J Clin Invest 118:3790–3797 [PMC free article] [PubMed]
  • Olsson R, Carlsson PO 2006 The pancreatic islet endothelial cell: emerging roles in islet function and disease. Int J Biochem Cell Biol 38:710–714 [PubMed]
  • Jansson L, Hellerström C 1983 Stimulation by glucose of the blood flow to the pancreatic islets of the rat. Diabetologia 25:45–50 [PubMed]
  • Jansson L, Andersson A, Bodin B, Källskog O 2007 Pancreatic islet blood flow during euglycaemic, hyperinsulinaemic clamp in anaesthetized rats. Acta Physiol (Oxf) 189:319–324 [PubMed]
  • Carlsson PO, Olsson R, Källskog O, Bodin B, Andersson A, Jansson L 2002 Glucose-induced islet blood flow increase in rats: interaction between nervous and metabolic mediators. Am J Physiol Endocrinol Metab 283:E457–E464 [PubMed]
  • Ballian N, Brunicardi FC 2007 Islet vasculature as a regulator of endocrine pancreas function. World J Surg 31:705–714 [PubMed]
  • Carlsson PO, Iwase M, Jansson L 1999 Stimulation of intestinal glucoreceptors in rats increases pancreatic islet blood flow through vagal mechanisms. Am J Physiol 276:R233–R236 [PubMed]
  • Brunicardi FC, Dyen Y, Brostrom L, Kleinman R, Colonna J, Gelabert H, Gingerich R 2000 The circulating hormonal milieu of the endocrine pancreas in healthy individuals, organ donors, and the isolated perfused human pancreas. Pancreas 21:203–211 [PubMed]
  • Lammert E, Cleaver O, Melton D 2001 Induction of pancreatic differentiation by signals from blood vessels. Science 294:564–567 [PubMed]
  • Yoshitomi H, Zaret KS 2004 Endothelial cell interactions initiate dorsal pancreas development by selectively inducing the transcription factor Ptf1a. Development 131:807–817 [PubMed]
  • Edsbagge J, Johansson JK, Esni F, Luo Y, Radice GL, Semb H 2005 Vascular function and sphingosine-1-phosphate regulate development of the dorsal pancreatic mesenchyme. Development 132:1085–1092 [PubMed]
  • Jacquemin P, Yoshitomi H, Kashima Y, Rousseau GG, Lemaigre FP, Zaret KS 2006 An endothelial-mesenchymal relay pathway regulates early phases of pancreas development. Dev Biol 290:189–199 [PubMed]
  • Johansson M, Andersson A, Carlsson PO, Jansson L 2006 Perinatal development of the pancreatic islet microvasculature in rats. J Anat 208:191–196 [PMC free article] [PubMed]
  • Cai Q, Brissova M, Shostak A, Powers AC 2009 Increased expression of VEGF-A in β-cells increases endothelial cells but impairs islet morphogenesis and postnatal β-cell growth. Diabetes 58(S1):A56 (Abstract)
  • Lammert E, Gu G, McLaughlin M, Brown D, Brekken R, Murtaugh LC, Gerber HP, Ferrara N, Melton DA 2003 Role of VEGF-A in vascularization of pancreatic islets. Curr Biol 13:1070–1074 [PubMed]
  • Brissova M, Shostak A, Shiota M, Wiebe PO, Poffenberger G, Kantz J, Chen Z, Carr C, Jerome WG, Chen J, Baldwin HS, Nicholson W, Bader DM, Jetton T, Gannon M, Powers AC 2006 Pancreatic islet production of vascular endothelial growth factor-a is essential for islet vascularization, revascularization, and function. Diabetes 55:2974–2985 [PubMed]
  • Iwashita N, Uchida T, Choi JB, Azuma K, Ogihara T, Ferrara N, Gerber H, Kawamori R, Inoue M, Watada H 2007 Impaired insulin secretion in vivo but enhanced insulin secretion from isolated islets in pancreatic β cell-specific vascular endothelial growth factor-A knock-out mice. Diabetologia 50:380–389 [PubMed]
  • Reinert RB, Brissova M, Kantz J, Powers AC 2009 Islet-derived vascular endothelial growth factor-A (VEGF-A) is important for maintenance of islet vasculature and function in adult mice. Diabetes 58(S1):A56 (Abstract)
  • Toyofuku Y, Uchida T, Nakayama S, Hirose T, Kawamori R, Fujitani Y, Inoue M, Watada H 2009 Normal islet vascularization is dispensable for expansion of β-cell mass in response to high-fat diet induced insulin resistance. Biochem Biophys Res Commun 383:303–307 [PubMed]
  • Branda CS, Dymecki SM 2004 Talking about a revolution: the impact of site-specific recombinases on genetic analyses in mice. Dev Cell 6:7–28 [PubMed]
  • Inoue M, Hager JH, Ferrara N, Gerber HP, Hanahan D 2002 VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic β-cell carcinogenesis. Cancer Cell 1:193–202 [PubMed]
  • Annerén C, Welsh M, Jansson L 2007 Glucose intolerance and reduced islet blood flow in transgenic mice expressing the FRK tyrosine kinase under the control of the rat insulin promoter. Am J Physiol Endocrinol Metab 292:E1183–E1190 [PubMed]
  • Cantley J, Selman C, Shukla D, Abramov AY, Forstreuter F, Esteban MA, Claret M, Lingard SJ, Clements M, Harten SK, Asare-Anane H, Batterham RL, Herrera PL, Persaud SJ, Duchen MR, Maxwell PH, Withers DJ 2009 Deletion of the von Hippel-Lindau gene in pancreatic β cells impairs glucose homeostasis in mice. J Clin Invest 119:125–135 [PMC free article] [PubMed]
  • Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL 1996 Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613 [PMC free article] [PubMed]
  • Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro SM, Lawler J, Hynes RO, Boivin GP, Bouck N 1998 Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell 93:1159–1170 [PubMed]
  • Li X, Zhang L, Meshinchi S, Dias-Leme C, Raffin D, Johnson JD, Treutelaar MK, Burant CF 2006 Islet microvasculature in islet hyperplasia and failure in a model of type 2 diabetes. Diabetes 55:2965–2973 [PubMed]
  • Mizuno A, Noma Y, Kuwajima M, Murakami T, Zhu M, Shima K 1999 Changes in islet capillary angioarchitecture coincide with impaired B-cell function but not with insulin resistance in male Otsuka-Long-Evans-Tokushima fatty rats: dimorphism of the diabetic phenotype at an advanced age. Metabolism 48:477–483 [PubMed]
  • Carlsson PO, Jansson L, Ostenson CG, Källskog O 1997 Islet capillary blood pressure increase mediated by hyperglycemia in NIDDM GK rats. Diabetes 46:947–952 [PubMed]
  • Atef N, Ktorza A, Picon L, Pénicaud L 1992 Increased islet blood flow in obese rats: role of the autonomic nervous system. Am J Physiol 262:E736–E740 [PubMed]
  • Svensson AM, Abdel-Halim SM, Efendic S, Jansson L, Ostenson CG 1994 Pancreatic and islet blood flow in F1-hybrids of the non-insulin-dependent diabetic GK-Wistar rat. Eur J Endocrinol 130:612–616 [PubMed]
  • Carlsson PO, Andersson A, Jansson L 1998 Influence of age, hyperglycemia, leptin, and NPY on islet blood flow in obese-hyperglycemic mice. Am J Physiol 275:E594–E601 [PubMed]
  • Nakamura M, Kitamura H, Konishi S, Nishimura M, Ono J, Ina K, Shimada T, Takaki R 1995 The endocrine pancreas of spontaneously diabetic db/db mice: microangiopathy as revealed by transmission electron microscopy. Diabetes Res Clin Pract 30:89–100 [PubMed]
  • Duvillié B, Currie C, Chrones T, Bucchini D, Jami J, Joshi RL, Hill DJ 2002 Increased islet cell proliferation, decreased apoptosis, and greater vascularization leading to β-cell hyperplasia in mutant mice lacking insulin. Endocrinology 143:1530–1537 [PubMed]
  • Jiang FX, Naselli G, Harrison LC 2002 Distinct distribution of laminin and its integrin receptors in the pancreas. J Histochem Cytochem 50:1625–1632 [PubMed]
  • Nikolova G, Jabs N, Konstantinova I, Domogatskaya A, Tryggvason K, Sorokin L, Fässler R, Gu G, Gerber HP, Ferrara N, Melton DA, Lammert E 2006 The vascular basement membrane: a niche for insulin gene expression and β cell proliferation. Dev Cell 10:397–405 [PubMed]
  • Johansson A, Lau J, Sandberg M, Borg LA, Magnusson PU, Carlsson PO 2009 Endothelial cell signalling supports pancreatic β cell function in the rat. Diabetologia 52:2385–2394 [PubMed]
  • Johansson M, Mattsson G, Andersson A, Jansson L, Carlsson PO 2006 Islet endothelial cells and pancreatic β-cell proliferation: studies in vitro and during pregnancy in adult rats. Endocrinology 147:2315–2324 [PubMed]
  • Virtanen I, Banerjee M, Palgi J, Korsgren O, Lukinius A, Thornell LE, Kikkawa Y, Sekiguchi K, Hukkanen M, Konttinen YT, Otonkoski T 2008 Blood vessels of human islets of Langerhans are surrounded by a double basement membrane. Diabetologia 51:1181–1191 [PubMed]
  • Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV 2000 Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343:230–238 [PubMed]
  • Shapiro AM, Nanji SA, Lakey JR 2003 Clinical islet transplant: current and future directions towards tolerance. Immunol Rev 196:219–236 [PubMed]
  • Merani S, Shapiro AM 2006 Current status of pancreatic islet transplantation. Clin Sci (Lond) 110:611–625 [PubMed]
  • Lukinius A, Jansson L, Korsgren O 1995 Ultrastructural evidence for blood microvessels devoid of an endothelial cell lining in transplanted pancreatic islets. Am J Pathol 146:429–435 [PMC free article] [PubMed]
  • Brissova M, Powers AC 2008 Revascularization of transplanted islets: can it be improved? Diabetes 57:2269–2271 [PMC free article] [PubMed]
  • Parr EL, Bowen KM, Lafferty KJ 1980 Cellular changes in cultured mouse thyroid glands and islets of Langerhans. Transplantation 30:135–141 [PubMed]
  • Carlsson PO, Palm F, Andersson A, Liss P 2001 Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site. Diabetes 50:489–495 [PubMed]
  • Mattsson G, Jansson L, Carlsson PO 2002 Decreased vascular density in mouse pancreatic islets after transplantation. Diabetes 51:1362–1366 [PubMed]
  • Davalli AM, Ogawa Y, Scaglia L, Wu YJ, Hollister J, Bonner-Weir S, Weir GC 1995 Function, mass, and replication of porcine and rat islets transplanted into diabetic nude mice. Diabetes 44:104–111 [PubMed]
  • Davalli AM, Scaglia L, Zangen DH, Hollister J, Bonner-Weir S, Weir GC 1996 Vulnerability of islets in the immediate posttransplantation period. Dynamic changes in structure and function. Diabetes 45:1161–1167 [PubMed]
  • Miao G, Ostrowski RP, Mace J, Hough J, Hopper A, Peverini R, Chinnock R, Zhang J, Hathout E 2006 Dynamic production of hypoxia-inducible factor-1α in early transplanted islets. Am J Transplant 6:2636–2643 [PubMed]
  • Carmeliet P, Dor Y, Herbert JM, Fukumura D, Brusselmans K, Dewerchin M, Neeman M, Bono F, Abramovitch R, Maxwell P, Koch CJ, Ratcliffe P, Moons L, Jain RK, Collen D, Keshert E, Keshet E 1998 Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490 [PubMed]
  • Linn T, Schneider K, Hammes HP, Preissner KT, Brandhorst H, Morgenstern E, Kiefer F, Bretzel RG 2003 Angiogenic capacity of endothelial cells in islets of Langerhans. FASEB J 17:881–883 [PubMed]
  • Brissova M, Fowler M, Wiebe P, Shostak A, Shiota M, Radhika A, Lin PC, Gannon M, Powers AC 2004 Intraislet endothelial cells contribute to revascularization of transplanted pancreatic islets. Diabetes 53:1318–1325 [PubMed]
  • Nyqvist D, Köhler M, Wahlstedt H, Berggren PO 2005 Donor islet endothelial cells participate in formation of functional vessels within pancreatic islet grafts. Diabetes 54:2287–2293 [PubMed]
  • Zhang N, Richter A, Suriawinata J, Harbaran S, Altomonte J, Cong L, Zhang H, Song K, Meseck M, Bromberg J, Dong H 2004 Elevated vascular endothelial growth factor production in islets improves islet graft vascularization. Diabetes 53:963–970 [PubMed]
  • Narang AS, Cheng K, Henry J, Zhang C, Sabek O, Fraga D, Kotb M, Gaber AO, Mahato RI 2004 Vascular endothelial growth factor gene delivery for revascularization in transplanted human islets. Pharm Res 21:15–25 [PubMed]
  • Lai Y, Schneider D, Kidszun A, Hauck-Schmalenberger I, Breier G, Brandhorst D, Brandhorst H, Iken M, Brendel MD, Bretzel RG, Linn T 2005 Vascular endothelial growth factor increases functional β-cell mass by improvement of angiogenesis of isolated human and murine pancreatic islets. Transplantation 79:1530–1536 [PubMed]
  • Su D, Zhang N, He J, Qu S, Slusher S, Bottino R, Bertera S, Bromberg J, Dong HH 2007 Angiopoietin-1 production in islets improves islet engraftment and protects islets from cytokine-induced apoptosis. Diabetes 56:2274–2283 [PubMed]
  • Olerud J, Johansson M, Lawler J, Welsh N, Carlsson PO 2008 Improved vascular engraftment and graft function after inhibition of the angiostatic factor thrombospondin-1 in mouse pancreatic islets. Diabetes 57:1870–1877 [PMC free article] [PubMed]
  • Johansson M, Olerud J, Jansson L, Carlsson PO 2009 Prolactin treatment improves engraftment and function of transplanted pancreatic islets. Endocrinology 150:1646–1653 [PubMed]
  • Johansson U, Rasmusson I, Niclou SP, Forslund N, Gustavsson L, Nilsson B, Korsgren O, Magnusson PU 2008 Formation of composite endothelial cell-mesenchymal stem cell islets: a novel approach to promote islet revascularization. Diabetes 57:2393–2401 [PMC free article] [PubMed]
  • Speier S, Nyqvist D, Cabrera O, Yu J, Molano RD, Pileggi A, Moede T, Köhler M, Wilbertz J, Leibiger B, Ricordi C, Leibiger IB, Caicedo A, Berggren PO 2008 Noninvasive in vivo imaging of pancreatic islet cell biology. Nat Med 14:574–578 [PMC free article] [PubMed]
  • DeFronzo RA, Gunnarsson R, Björkman O, Olsson M, Wahren J 1985 Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 76:149–155 [PMC free article] [PubMed]
  • Björntorp P, Berchtold P, Holm J, Larsson B 1971 The glucose uptake of human adipose tissue in obesity. Eur J Clin Invest 1:480–485 [PubMed]
  • Björntorp P, Krotkiewski M, Larsson B, Somlo-Szücs Z 1970 Effects of feeding states on lipid radioactivity in liver, muscle and adipose tissue after injection of labelled glucose in the rat. Acta Physiol Scand 80:29–38 [PubMed]
  • Lillioja S, Young AA, Culter CL, Ivy JL, Abbott WG, Zawadzki JK, Yki-Järvinen H, Christin L, Secomb TW, Bogardus C 1987 Skeletal muscle capillary density and fiber type are possible determinants of in vivo insulin resistance in man. J Clin Invest 80:415–424 [PMC free article] [PubMed]
  • Ogihara T, Shin BC, Anai M, Katagiri H, Inukai K, Funaki M, Fukushima Y, Ishihara H, Takata K, Kikuchi M, Yazaki Y, Oka Y, Asano T 1997 Insulin receptor substrate (IRS)-2 is dephosphorylated more rapidly than IRS-1 via its association with phosphatidylinositol 3-kinase in skeletal muscle cells. J Biol Chem 272:12868–12873 [PubMed]
  • Sarabia V, Lam L, Burdett E, Leiter LA, Klip A 1992 Glucose transport in human skeletal muscle cells in culture. Stimulation by insulin and metformin. J Clin Invest 90:1386–1395 [PMC free article] [PubMed]
  • Sarabia V, Ramlal T, Klip A 1990 Glucose uptake in human and animal muscle cells in culture. Biochem Cell Biol 68:536–542 [PubMed]
  • Yang YJ, Hope ID, Ader M, Bergman RN 1989 Insulin transport across capillaries is rate limiting for insulin action in dogs. J Clin Invest 84:1620–1628 [PMC free article] [PubMed]
  • Chiu JD, Richey JM, Harrison LN, Zuniga E, Kolka CM, Kirkman E, Ellmerer M, Bergman RN 2008 Direct administration of insulin into skeletal muscle reveals that the transport of insulin across the capillary endothelium limits the time course of insulin to activate glucose disposal. Diabetes 57:828–835 [PubMed]
  • Wang H, Liu Z, Li G, Barrett EJ 2006 The vascular endothelial cell mediates insulin transport into skeletal muscle. Am J Physiol Endocrinol Metab 291:E323–E332 [PubMed]
  • Dernovsek KD, Bar RS 1985 Processing of cell-bound insulin by capillary and macrovascular endothelial cells in culture. Am J Physiol 248:E244–E251 [PubMed]
  • Jialal I, King GL, Buchwald S, Kahn CR, Crettaz M 1984 Processing of insulin by bovine endothelial cells in culture. Internalization without degradation. Diabetes 33:794–800 [PubMed]
  • Renkin EM, Wiig H 1994 Limits to steady-state lymph flow rates derived from plasma-to-tissue uptake measurements. Microvasc Res 47:318–328 [PubMed]
  • Kolka CM, Harrison LN, Lottati M, Kirkman EL, Bergman RN 2009 Diet-induced obesity reduces insulin access to skeletal muscle causing insulin resistance. Diabetes 58 (S1):A68 (Abstract)
  • Miles PD, Levisetti M, Reichart D, Khoursheed M, Moossa AR, Olefsky JM 1995 Kinetics of insulin action in vivo. Identification of rate-limiting steps. Diabetes 44:947–953 [PubMed]
  • Yang YJ, Hope I, Ader M, Poulin RA, Bergman RN 1992 Dose-response relationship between lymph insulin and glucose uptake reveals enhanced insulin sensitivity of peripheral tissues. Diabetes 41:241–253 [PubMed]
  • King GL, Johnson SM 1985 Receptor-mediated transport of insulin across endothelial cells. Science 227:1583–1586 [PubMed]
  • Bar RS, Siddle K, Dolash S, Boes M, Dake B 1988 Actions of insulin and insulin like growth factors I and II in cultured microvessel endothelial cells from bovine adipose tissue. Metabolism 37:714–720 [PubMed]
  • Steil GM, Ader M, Moore DM, Rebrin K, Bergman RN 1996 Transendothelial insulin transport is not saturable in vivo. No evidence for a receptor-mediated process. J Clin Invest 97:1497–1503 [PMC free article] [PubMed]
  • Hamilton-Wessler M, Ader M, Dea MK, Moore D, Loftager M, Markussen J, Bergman RN 2002 Mode of transcapillary transport of insulin and insulin analog NN304 in dog hindlimb: evidence for passive diffusion. Diabetes 51:574–582 [PubMed]
  • Wang H, Wang AX, Liu Z, Barrett EJ 2008 Insulin signaling stimulates insulin transport by bovine aortic endothelial cells. Diabetes 57:540–547 [PubMed]
  • Bar RS, Boes M, Sandra A 1988 Vascular transport of insulin to rat cardiac muscle. Central role of the capillary endothelium. J Clin Invest 81:1225–1233 [PMC free article] [PubMed]
  • Baron AD 1994 Hemodynamic actions of insulin. Am J Physiol 267:E187–E202 [PubMed]
  • Baron AD, Laakso M, Brechtel G, Edelman SV 1991 Mechanism of insulin resistance in insulin-dependent diabetes mellitus: a major role for reduced skeletal muscle blood flow. J Clin Endocrinol Metab 73:637–643 [PubMed]
  • Laakso M, Edelman SV, Brechtel G, Baron AD 1990 Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance. J Clin Invest 85:1844–1852 [PMC free article] [PubMed]
  • Laakso M, Edelman SV, Brechtel G, Baron AD 1992 Impaired insulin-mediated skeletal muscle blood flow in patients with NIDDM. Diabetes 41:1076–1083 [PubMed]
  • Vollenweider P, Tappy L, Randin D, Schneiter P, Jéquier E, Nicod P, Scherrer U 1993 Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans. J Clin Invest 92:147–154 [PMC free article] [PubMed]
  • Raitakari M, Knuuti MJ, Ruotsalainen U, Laine H, Mäkeä P, Teräs M, Sipilä H, Niskanen T, Raitakari OT, Iida H 1995 Insulin increases blood volume in human skeletal muscle: studies using [15O]CO and positron emission tomography. Am J Physiol 269:E1000–E1005 [PubMed]
  • Utriainen T, Nuutila P, Takala T, Vicini P, Ruotsalainen U, Rönnemaa T, Tolvanen T, Raitakari M, Haaparanta M, Kirvelä O, Cobelli C, Yki-Järvinen H 1997 Intact insulin stimulation of skeletal muscle blood flow, its heterogeneity and redistribution, but not of glucose uptake in non-insulin-dependent diabetes mellitus. J Clin Invest 100:777–785 [PMC free article] [PubMed]
  • Raitakari M, Nuutila P, Knuuti J, Raitakari OT, Laine H, Ruotsalainen U, Kirvelä O, Takala TO, Iida H, Yki-Järvinen H 1997 Effects of insulin on blood flow and volume in skeletal muscle of patients with IDDM: studies using [15O]H2O, [15O]CO, and positron emission tomography. Diabetes 46:2017–2021 [PubMed]
  • Tack CJ, Ong MK, Lutterman JA, Smits P 1998 Insulin-induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone. Diabetologia 41:569–576 [PubMed]
  • James DE, Burleigh KM, Storlien LH, Bennett SP, Kraegen EW 1986 Heterogeneity of insulin action in muscle: influence of blood flow. Am J Physiol 251:E422–E430 [PubMed]
  • Liang C, Doherty JU, Faillace R, Maekawa K, Arnold S, Gavras H, Hood Jr WB 1982 Insulin infusion in conscious dogs. Effects on systemic and coronary hemodynamics, regional blood flows, and plasma catecholamines. J Clin Invest 69:1321–1336 [PMC free article] [PubMed]
  • Fisher BM, Gillen G, Dargie HJ, Inglis GC, Frier BM 1987 The effects of insulin-induced hypoglycaemia on cardiovascular function in normal man: studies using radionuclide ventriculography. Diabetologia 30:841–845 [PubMed]
  • Creager MA, Liang CS, Coffman JD 1985 β-Adrenergic-mediated vasodilator response to insulin in the human forearm. J Pharmacol Exp Ther 235:709–714 [PubMed]
  • Richter EA, Mikines KJ, Galbo H, Kiens B 1989 Effect of exercise on insulin action in human skeletal muscle. J Appl Physiol 66:876–885 [PubMed]
  • DeFronzo RA, Jacot E, Jequier E, Maeder E, Wahren J, Felber JP 1981 The effect of insulin on the disposal of intravenous glucose. Results from indirect calorimetry and hepatic and femoral venous catheterization. Diabetes 30:1000–1007 [PubMed]
  • DeFronzo RA, Ferrannini E, Hendler R, Felig P, Wahren J 1983 Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes 32:35–45 [PubMed]
  • Jackson RA, Hamling JB, Blix PM, Sim BM, Hawa MI, Jaspan JB, Belin J, Nabarro JD 1986 The influence of graded hyperglycemia with and without physiological hyperinsulinemia on forearm glucose uptake and other metabolic responses in man. J Clin Endocrinol Metab 63:594–604 [PubMed]
  • Jackson RA, Roshania RD, Hawa MI, Sim BM, DiSilvio L 1986 Impact of glucose ingestion on hepatic and peripheral glucose metabolism in man: an analysis based on simultaneous use of the forearm and double isotope techniques. J Clin Endocrinol Metab 63:541–549 [PubMed]
  • Yki-Järvinen H, Young AA, Lamkin C, Foley JE 1987 Kinetics of glucose disposal in whole body and across the forearm in man. J Clin Invest 79:1713–1719 [PMC free article] [PubMed]
  • Taddei S, Virdis A, Mattei P, Natali A, Ferrannini E, Salvetti A 1995 Effect of insulin on acetylcholine-induced vasodilation in normotensive subjects and patients with essential hypertension. Circulation 92:2911–2918 [PubMed]
  • Bonadonna RC, Saccomani MP, Del Prato S, Bonora E, DeFronzo RA, Cobelli C 1998 Role of tissue-specific blood flow and tissue recruitment in insulin-mediated glucose uptake of human skeletal muscle. Circulation 98:234–241 [PubMed]
  • Natali A, Buzzigoli G, Taddei S, Santoro D, Cerri M, Pedrinelli R, Ferrannini E 1990 Effects of insulin on hemodynamics and metabolism in human forearm. Diabetes 39:490–500 [PubMed]
  • Yki-Järvinen H, Utriainen T 1998 Insulin-induced vasodilatation: physiology or pharmacology? Diabetologia 41:369–379 [PubMed]
  • Steinberg HO, Baron AD 1999 Insulin-mediated vasodilation: why one’s physiology could be the other’s pharmacology. Diabetologia 42:493–495 [PubMed]
  • Honig CR, Odoroff CL, Frierson JL 1982 Active and passive capillary control in red muscle at rest and in exercise. Am J Physiol 243:H196–H206 [PubMed]
  • Poole DC, Brown MD, Hudlicka O 2008 Counterpoint: There is not capillary recruitment in active skeletal muscle during exercise. J Appl Physiol 104:891–893; discussion 893–894 [PubMed]
  • Rattigan S, Clark MG, Barrett EJ 1997 Hemodynamic actions of insulin in rat skeletal muscle: evidence for capillary recruitment. Diabetes 46:1381–1388 [PubMed]
  • Coggins M, Lindner J, Rattigan S, Jahn L, Fasy E, Kaul S, Barrett E 2001 Physiologic hyperinsulinemia enhances human skeletal muscle perfusion by capillary recruitment. Diabetes 50:2682–2690 [PubMed]
  • Vincent MA, Barrett EJ, Lindner JR, Clark MG, Rattigan S 2003 Inhibiting NOS blocks microvascular recruitment and blunts muscle glucose uptake in response to insulin. Am J Physiol Endocrinol Metab 285:E123–E129 [PubMed]
  • Zhang L, Vincent MA, Richards SM, Clerk LH, Rattigan S, Clark MG, Barrett EJ 2004 Insulin sensitivity of muscle capillary recruitment in vivo. Diabetes 53:447–453 [PubMed]
  • Serné EH, IJzerman RG, Gans RO, Nijveldt R, De Vries G, Evertz R, Donker AJ, Stehouwer CD 2002 Direct evidence for insulin-induced capillary recruitment in skin of healthy subjects during physiological hyperinsulinemia. Diabetes 51:1515–1522 [PubMed]
  • Zeng G, Quon MJ 1996 Insulin-stimulated production of nitric oxide is inhibited by wortmannin. Direct measurement in vascular endothelial cells. J Clin Invest 98:894–898 [PMC free article] [PubMed]
  • Montagnani M, Chen H, Barr VA, Quon MJ 2001 Insulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179). J Biol Chem 276:30392–30398 [PubMed]
  • Eringa EC, Stehouwer CD, Merlijn T, Westerhof N, Sipkema P 2002 Physiological concentrations of insulin induce endothelin-mediated vasoconstriction during inhibition of NOS or PI3-kinase in skeletal muscle arterioles. Cardiovasc Res 56:464–471 [PubMed]
  • Kubota T, Kubota N, Kozono H, Takahashi T, Itoh S, Ueki K, Kadowaki T 2008 Insulin signaling in endothelial cells participates in the regulation of skeletal muscle insulin sensitivity. Diabetes 57(S1):A369 (Abstract)
  • Eringa EC, Stehouwer CD, Walburg K, Clark AD, van Nieuw Amerongen GP, Westerhof N, Sipkema P 2006 Physiological concentrations of insulin induce endothelin-dependent vasoconstriction of skeletal muscle resistance arteries in the presence of tumor necrosis factor-α dependence on c-Jun N-terminal kinase. Arterioscler Thromb Vasc Biol 26:274–280 [PubMed]
  • Eringa EC, Stehouwer CD, van Nieuw Amerongen GP, Ouwehand L, Westerhof N, Sipkema P 2004 Vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by ERK1/2 activation in endothelium. Am J Physiol Heart Circ Physiol 287:H2043–H2048 [PubMed]
  • Eringa EC, Stehouwer CD, Roos MH, Westerhof N, Sipkema P 2007 Selective resistance to vasoactive effects of insulin in muscle resistance arteries of obese Zucker (fa/fa) rats. Am J Physiol Endocrinol Metab 293:E1134–E1139 [PubMed]
  • Cardillo C, Campia U, Iantorno M, Panza JA 2004 Enhanced vascular activity of endogenous endothelin-1 in obese hypertensive patients. Hypertension 43:36–40 [PubMed]
  • Shankar RR, Wu Y, Shen HQ, Zhu JS, Baron AD 2000 Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance. Diabetes 49:684–687 [PubMed]
  • Wallis MG, Wheatley CM, Rattigan S, Barrett EJ, Clark AD, Clark MG 2002 Insulin-mediated hemodynamic changes are impaired in muscle of Zucker obese rats. Diabetes 51:3492–3498 [PubMed]
  • Clerk LH, Rattigan S, Clark MG 2002 Lipid infusion impairs physiologic insulin-mediated capillary recruitment and muscle glucose uptake in vivo. Diabetes 51:1138- 1145 [PubMed]
  • Rattigan S, Clark MG, Barrett EJ 1999 Acute vasoconstriction-induced insulin resistance in rat muscle in vivo. Diabetes 48:564–569 [PubMed]
  • Youd JM, Rattigan S, Clark MG 2000 Acute impairment of insulin-mediated capillary recruitment and glucose uptake in rat skeletal muscle in vivo by TNF-alpha. Diabetes 49:1904–1909 [PubMed]
  • Wallis MG, Smith ME, Kolka CM, Zhang L, Richards SM, Rattigan S, Clark MG 2005 Acute glucosamine-induced insulin resistance in muscle in vivo is associated with impaired capillary recruitment. Diabetologia 48:2131–2139 [PubMed]
  • Gudbjörnsdóttir S, Sjöstrand M, Strindberg L, Lönnroth P 2005 Decreased muscle capillary permeability surface area in type 2 diabetic subjects. J Clin Endocrinol Metab 90:1078–1082 [PubMed]
  • Lesniewski LA, Donato AJ, Behnke BJ, Woodman CR, Laughlin MH, Ray CA, Delp MD 2008 Decreased NO signaling leads to enhanced vasoconstrictor responsiveness in skeletal muscle arterioles of the ZDF rat prior to overt diabetes and hypertension. Am J Physiol Heart Circ Physiol 294:H1840–H1850 [PMC free article] [PubMed]
  • Savage DB, Petersen KF, Shulman GI 2007 Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev 87:507–520 [PMC free article] [PubMed]
  • Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI 2002 Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem 277:50230–50236 [PubMed]
  • Vicent D, Ilany J, Kondo T, Naruse K, Fisher SJ, Kisanuki YY, Bursell S, Yanagisawa M, King GL, Kahn CR 2003 The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance. J Clin Invest 111:1373–1380 [PMC free article] [PubMed]
  • Brüning JC, Michael MD, Winnay JN, Hayashi T, Hörsch D, Accili D, Goodyear LJ, Kahn CR 1998 A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 2:559–569 [PubMed]
  • Chisalita SI, Arnqvist HJ 2004 Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells. Am J Physiol Endocrinol Metab 286:E896–E901 [PubMed]
  • Clifford PS 2007 Skeletal muscle vasodilatation at the onset of exercise. J Physiol 583:825–833 [PMC free article] [PubMed]
  • Rattigan S, Wheatley C, Richards SM, Barrett EJ, Clark MG 2005 Exercise and insulin-mediated capillary recruitment in muscle. Exerc Sport Sci Rev 33:43–48 [PubMed]
  • Ross RM, Wadley GD, Clark MG, Rattigan S, McConell GK 2007 Local nitric oxide synthase inhibition reduces skeletal muscle glucose uptake but not capillary blood flow during in situ muscle contraction in rats. Diabetes 56:2885–2892 [PubMed]
  • Wheatley CM, Rattigan S, Richards SM, Barrett EJ, Clark MG 2004 Skeletal muscle contraction stimulates capillary recruitment and glucose uptake in insulin-resistant obese Zucker rats. Am J Physiol Endocrinol Metab 287:E804–E809 [PubMed]
  • Krueger M, Bechmann I 2010 CNS pericytes: concepts, misconceptions, and a way out. Glia 58:1–10 [PubMed]
  • Bergers G, Song S 2005 The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol 7:452–464 [PMC free article] [PubMed]
  • Gerhardt H, Semb H 2008 Pericytes: gatekeepers in tumour cell metastasis? J Mol Med 86:135–144 [PubMed]
  • Gaengel K, Genové G, Armulik A, Betsholtz C 2009 Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 29:630–638 [PubMed]
  • Armulik A, Abramsson A, Betsholtz C 2005 Endothelial/pericyte interactions. Circ Res 97:512–523 [PubMed]
  • Mandarino LJ, Sundarraj N, Finlayson J, Hassell HR 1993 Regulation of fibronectin and laminin synthesis by retinal capillary endothelial cells and pericytes in vitro. Exp Eye Res 57:609–621 [PubMed]
  • Suematsu M, Aiso S 2001 Professor Toshio Ito: a clairvoyant in pericyte biology. Keio J Med 50:66–71 [PubMed]
  • Balabanov R, Dore-Duffy P 1998 Role of the CNS microvascular pericyte in the blood-brain barrier. J Neurosci Res 53:637–644 [PubMed]
  • Kunz J, Krause D, Gehrmann J, Dermietzel R 1995 Changes in the expression pattern of blood-brain barrier-associated pericytic aminopeptidase N (pAP N) in the course of acute experimental autoimmune encephalomyelitis. J Neuroimmunol 59:41–55 [PubMed]
  • Rucker HK, Wynder HJ, Thomas WE 2000 Cellular mechanisms of CNS pericytes. Brain Res Bull 51:363–369 [PubMed]
  • Hellström M, Gerhardt H, Kalén M, Li X, Eriksson U, Wolburg H, Betsholtz C 2001 Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol 153:543–553 [PMC free article] [PubMed]
  • Gerhardt H, Betsholtz C 2003 Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res 314:15–23 [PubMed]
  • Ozerdem U, Grako KA, Dahlin-Huppe K, Monosov E, Stallcup WB 2001 NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev Dyn 222:218–227 [PubMed]
  • Ozerdem U, Stallcup WB 2003 Early contribution of pericytes to angiogenic sprouting and tube formation. Angiogenesis 6:241–249 [PMC free article] [PubMed]
  • Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C 2003 VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161:1163–1177 [PMC free article] [PubMed]
  • Redmer DA, Doraiswamy V, Bortnem BJ, Fisher K, Jablonka-Shariff A, Grazul-Bilska AT, Reynolds LP 2001 Evidence for a role of capillary pericytes in vascular growth of the developing ovine corpus luteum. Biol Reprod 65:879–889 [PubMed]
  • Evensen L, Micklem DR, Blois A, Berge SV, Aarsaether N, Littlewood-Evans A, Wood J, Lorens JB 2009 Mural cell associated VEGF is required for organotypic vessel formation. PLoS One 4:e5798 [PMC free article] [PubMed]
  • Reigstad LJ, Sande HM, Fluge Ø, Bruland O, Muga A, Varhaug JE, Martinez A, Lillehaug JR 2003 Platelet- derived growth factor (PDGF)-C, a PDGF family member with a vascular endothelial growth factor-like structure. J Biol Chem 278:17114–17120 [PubMed]
  • Andrae J, Gallini R, Betsholtz C 2008 Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22:1276–1312 [PMC free article] [PubMed]
  • Kohler N, Lipton A 1974 Platelets as a source of fibroblast growth-promoting activity. Exp Cell Res 87:297–301 [PubMed]
  • Ross R, Glomset J, Kariya B, Harker L 1974 A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci USA 71:1207–1210 [PMC free article] [PubMed]
  • Westermark B, Wasteson A 1976 A platelet factor stimulating human normal glial cells. Exp Cell Res 98:170–174 [PubMed]
  • Antoniades HN, Scher CD, Stiles CD 1979 Purification of human platelet-derived growth factor. Proc Natl Acad Sci USA 76:1809–1813 [PMC free article] [PubMed]
  • Deuel TF, Huang JS, Proffitt RT, Baenziger JU, Chang D, Kennedy BB 1981 Human platelet-derived growth factor. Purification and resolution into two active protein fractions. J Biol Chem 256:8896–8899 [PubMed]
  • Heldin CH, Westermark B, Wasteson A 1979 Platelet-derived growth factor: purification and partial characterization. Proc Natl Acad Sci USA 76:3722–3726 [PMC free article] [PubMed]
  • Raines EW, Ross R 1982 Platelet-derived growth factor. I. High yield purification and evidence for multiple forms. J Biol Chem 257:5154–5160 [PubMed]
  • Heldin CH, Westermark B 1999 Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79:1283–1316 [PubMed]
  • Kelly JD, Haldeman BA, Grant FJ, Murray MJ, Seifert RA, Bowen-Pope DF, Cooper JA, Kazlauskas A 1991 Platelet-derived growth factor (PDGF) stimulates PDGF receptor subunit dimerization and intersubunit trans-phosphorylation. J Biol Chem 266:8987–8992 [PubMed]
  • Kazlauskas A, Cooper JA 1989 Autophosphorylation of the PDGF receptor in the kinase insert region regulates interactions with cell proteins. Cell 58:1121–1133 [PubMed]
  • Hoch RV, Soriano P 2003 Roles of PDGF in animal development. Development 130:4769–4784 [PubMed]
  • Tallquist MD, French WJ, Soriano P 2003 Additive effects of PDGF receptor β signaling pathways in vascular smooth muscle cell development. PLoS Biol 1:E52 [PMC free article] [PubMed]
  • Heldin CH, Wasteson A, Westermark B 1982 Interaction of platelet-derived growth factor with its fibroblast receptor. Demonstration of ligand degradation and receptor modulation. J Biol Chem 257:4216–4221 [PubMed]
  • Sorkin A, Westermark B, Heldin CH, Claesson-Welsh L 1991 Effect of receptor kinase inactivation on the rate of internalization and degradation of PDGF and the PDGF β-receptor. J Cell Biol 112:469–478 [PMC free article] [PubMed]
  • Mori S, Kanaki H, Tanaka K, Morisaki N, Saito Y 1995 Ligand-activated platelet-derived growth factor β-receptor is degraded through proteasome-dependent proteolytic pathway. Biochem Biophys Res Commun 217:224–229 [PubMed]
  • LaRochelle WJ, May-Siroff M, Robbins KC, Aaronson SA 1991 A novel mechanism regulating growth factor association with the cell surface: identification of a PDGF retention domain. Genes Dev 5:1191–1199 [PubMed]
  • Ostman A, Andersson M, Betsholtz C, Westermark B, Heldin CH 1991 Identification of a cell retention signal in the B-chain of platelet-derived growth factor and in the long splice version of the A-chain. Cell Regul 2:503–512 [PMC free article] [PubMed]
  • Raines EW, Ross R 1992 Compartmentalization of PDGF on extracellular binding sites dependent on exon-6-encoded sequences. J Cell Biol 116:533–543 [PMC free article] [PubMed]
  • Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellstrom M, Backstrom G, Fredriksson S, Landegren U, Nystrom HC, Bergstrom G, Dejana E, Ostman A, Lindahl P, Betsholtz C 2003 Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev 17:1835–1840 [PMC free article] [PubMed]
  • Lindahl P, Johansson BR, Levéen P, Betsholtz C 1997 Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277:242–245 [PubMed]
  • Hellström M, Kalén M, Lindahl P, Abramsson A, Betsholtz C 1999 Role of PDGF-B and PDGFR-β in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126:3047–3055 [PubMed]
  • Levéen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E, Betsholtz C 1994 Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev 8:1875–1887 [PubMed]
  • Soriano P 1994 Abnormal kidney development and hematological disorders in PDGF β-receptor mutant mice. Genes Dev 8:1888–1896 [PubMed]
  • Hirschi KK, Rohovsky SA, D'Amore PA 1998 PDGF, TGF-β, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. J Cell Biol 141:805–814 [PMC free article] [PubMed]
  • Hirschi KK, Rohovsky SA, Beck LH, Smith SR, D'Amore PA 1999 Endothelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact. Circ Res 84:298–305 [PubMed]
  • Tilton RG, Kilo C, Williamson JR 1979 Pericyte-endothelial relationships in cardiac and skeletal muscle capillaries. Microvasc Res 18:325–335 [PubMed]
  • Egginton S, Hudlicka O, Brown MD, Graciotti L, Granata AL 1996 In vivo pericyte-endothelial cell interaction during angiogenesis in adult cardiac and skeletal muscle. Microvasc Res 51:213–228 [PubMed]
  • Raines S, Richards O, Scheuler K, Attie A 2009 Decrease in PDGF-B signalling reduces in vivo insulin secretion. Diabetes 58(S1):A376 (Abstract)
  • Welsh M, Claesson-Welsh L, Hallberg A, Welsh N, Betsholtz C, Arkhammar P, Nilsson T, Heldin CH, Berggren PO 1990 Coexpression of the platelet-derived growth factor (PDGF) B chain and the PDGF β receptor in isolated pancreatic islet cells stimulates DNA synthesis. Proc Natl Acad Sci USA 87:5807–5811 [PMC free article] [PubMed]
  • Hammes HP 2005 Pericytes and the pathogenesis of diabetic retinopathy. Horm Metab Res 37(Suppl 1):39–43 [PubMed]
  • Geraldes P, Hiraoka-Yamamoto J, Matsumoto M, Clermont A, Leitges M, Marette A, Aiello LP, Kern TS, King GL 2009 Activation of PKC-δ and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy. Nat Med 15:1298–1306 [PMC free article] [PubMed]
  • Wolf G, Chen S, Ziyadeh FN 2005 From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes 54:1626–1634 [PubMed]
  • Siemionow M, Demir Y 2004 Diabetic neuropathy: pathogenesis and treatment. J Reconstr Microsurg 20:241–252 [PubMed]
  • Tilton RG, Hoffmann PL, Kilo C, Williamson JR 1981 Pericyte degeneration and basement membrane thickening in skeletal muscle capillaries of human diabetics. Diabetes 30:326–334 [PubMed]
  • Caplan AI 1994 The mesengenic process. Clin Plast Surg 21:429–435 [PubMed]
  • Hess D, Li L, Martin M, Sakano S, Hill D, Strutt B, Thyssen S, Gray DA, Bhatia M 2003 Bone marrow-derived stem cells initiate pancreatic regeneration. Nat Biotechnol 21:763–770 [PubMed]
  • Ianus A, Holz GG, Theise ND, Hussain MA 2003 In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 111:843–850 [PMC free article] [PubMed]
  • Voltarelli JC, Couri CE, Stracieri AB, Oliveira MC, Moraes DA, Pieroni F, Coutinho M, Malmegrim KC, Foss-Freitas MC, Simões BP, Foss MC, Squiers E, Burt RK 2007 Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 297:1568–1576 [PubMed]
  • Choi JB, Uchino H, Azuma K, Iwashita N, Tanaka Y, Mochizuki H, Migita M, Shimada T, Kawamori R, Watada H 2003 Little evidence of transdifferentiation of bone marrow-derived cells into pancreatic β cells. Diabetologia 46:1366–1374 [PubMed]
  • Lechner A, Yang YG, Blacken RA, Wang L, Nolan AL, Habener JF 2004 No evidence for significant transdifferentiation of bone marrow into pancreatic β-cells in vivo. Diabetes 53:616–623 [PubMed]
  • Ezquer FE, Ezquer ME, Parrau DB, Carpio D, Yañez AJ, Conget PA 2008 Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant 14:631–640 [PubMed]
  • Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Péault B 2008 A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301–313 [PubMed]
  • Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer RE, Tallquist MD, Graff JM 2008 White fat progenitor cells reside in the adipose vasculature. Science 322:583–586 [PMC free article] [PubMed]
  • Dai C, Brissova M, Nyman LR, Shiota M, Powers AC 2009 Islet vasculature changes in response to insulin resistance. Diabetes 58(S1):A57 (Abstract)
  • Hayden MR, Karuparthi PR, Habibi J, Wasekar C, Lastra G, Manrique C, Stas S, Sowers JR 2007 Ultrastructural islet study of early fibrosis in the Ren2 rat model of hypertension. Emerging role of the islet pancreatic pericyte-stellate cell. JOP 8:725–738 [PubMed]
  • Hayden MR, Karuparthi PR, Habibi J, Lastra G, Patel K, Wasekar C, Manrique CM, Ozerdem U, Stas S, Sowers JR 2008 Ultrastructure of islet microcirculation, pericytes and the islet exocrine interface in the HIP rat model of diabetes. Exp Biol Med (Maywood) 233:1109–1123 [PMC free article] [PubMed]
  • Hayden MR, Patel K, Habibi J, Gupta D, Tekwani SS, Whaley-Connell A, Sowers JR 2008 Attenuation of endocrine-exocrine pancreatic communication in type 2 diabetes: pancreatic extracellular matrix ultrastructural abnormalities. J Cardiometab Syndr 3:234–243 [PMC free article] [PubMed]
  • Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D 2003 Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 111:1287–1295 [PMC free article] [PubMed]
  • Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM 2003 Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol 163:1801–1815 [PMC free article] [PubMed]
  • Joyce JA, Laakkonen P, Bernasconi M, Bergers G, Ruoslahti E, Hanahan D 2003 Stage-specific vascular markers revealed by phage display in a mouse model of pancreatic islet tumorigenesis. Cancer Cell 4:393–403 [PubMed]
  • Berger M, Bergers G, Arnold B, Hämmerling GJ, Ganss R 2005 Regulator of G-protein signaling-5 induction in pericytes coincides with active vessel remodeling during neovascularization. Blood 105:1094–1101 [PubMed]
  • Pietras K, Hanahan D 2005 A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23:939–952 [PubMed]
  • Xian X, Håkansson J, Ståhlberg A, Lindblom P, Betsholtz C, Gerhardt H, Semb H 2006 Pericytes limit tumor cell metastasis. J Clin Invest 116:642–651 [PMC free article] [PubMed]
  • Song S, Ewald AJ, Stallcup W, Werb Z, Bergers G 2005 PDGFRβ+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 7:870–879 [PMC free article] [PubMed]
  • Sennino B, Falcón BL, McCauley D, Le T, McCauley T, Kurz JC, Haskell A, Epstein DM, McDonald DM 2007 Sequential loss of tumor vessel pericytes and endothelial cells after inhibition of platelet-derived growth factor B by selective aptamer AX102. Cancer Res 67:7358–7367 [PubMed]
  • Yonenaga Y, Mori A, Onodera H, Yasuda S, Oe H, Fujimoto A, Tachibana T, Imamura M 2005 Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncology 69:159–166 [PubMed]
  • Whiteman EL, Chen JJ, Birnbaum MJ 2003 Platelet-derived growth factor (PDGF) stimulates glucose transport in 3T3–L1 adipocytes overexpressing PDGF receptor by a pathway independent of insulin receptor substrates. Endocrinology 144:3811–3820 [PubMed]
  • Yuasa T, Kakuhata R, Kishi K, Obata T, Shinohara Y, Bando Y, Izumi K, Kajiura F, Matsumoto M, Ebina Y 2004 Platelet-derived growth factor stimulates glucose transport in skeletal muscles of transgenic mice specifically expressing platelet-derived growth factor receptor in the muscle, but it does not affect blood glucose levels. Diabetes 53:2776–2786 [PubMed]
  • Hoehn KL, Hohnen-Behrens C, Cederberg A, Wu LE, Turner N, Yuasa T, Ebina Y, James DE 2008 IRS1-independent defects define major nodes of insulin resistance. Cell Metab 7:421–433 [PMC free article] [PubMed]
  • Druker BJ 2002 STI571 (Gleevec) as a paradigm for cancer therapy. Trends Mol Med 8:S14–S18 [PubMed]
  • Veneri D, Franchini M, Bonora E 2005 Imatinib and regression of type 2 diabetes. N Engl J Med 352:1049–1050 [PubMed]
  • Breccia M, Muscaritoli M, Aversa Z, Mandelli F, Alimena G 2004 Imatinib mesylate may improve fasting blood glucose in diabetic Ph+ chronic myelogenous leukemia patients responsive to treatment. J Clin Oncol 22:4653–4655 [PubMed]
  • Breccia M, Muscaritoli M, Alimena G 2005 Reduction of glycosylated hemoglobin with stable insulin levels in a diabetic patient with chronic myeloid leukemia responsive to imatinib. Haematologica 90 Suppl:ECR21 [PubMed]
  • Dingli D, Wolf RC, Vella A 2007 Imatinib and type 2 diabetes. Endocr Pract 13:126–130 [PubMed]
  • Han MS, Chung KW, Cheon HG, Rhee SD, Yoon CH, Lee MK, Kim KW, Lee MS 2009 Imatinib mesylate reduces endoplasmic reticulum stress and induces remission of diabetes in db/db mice. Diabetes 58:329–336 [PMC free article] [PubMed]
  • Louvet C, Szot GL, Lang J, Lee MR, Martinier N, Bollag G, Zhu S, Weiss A, Bluestone JA 2008 Tyrosine kinase inhibitors reverse type 1 diabetes in nonobese diabetic mice. Proc Natl Acad Sci USA 105:18895–18900 [PMC free article] [PubMed]
  • Kano MR, Komuta Y, Iwata C, Oka M, Shirai YT, Morishita Y, Ouchi Y, Kataoka K, Miyazono K 2009 Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-β receptor inhibitor on extravasation of nanoparticles from neovasculature. Cancer Sci 100:173–180 [PubMed]
  • Cersosimo E, DeFronzo RA 2006 Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diabetes Metab Res Rev 22:423–436 [PubMed]
  • Murad F 2008 Nitric oxide and cyclic guanosine monophosphate signaling in the eye. Can J Ophthalmol 43: 291–294 [PubMed]
  • Brunner F, Brás-Silva C, Cerdeira AS, Leite-Moreira AF 2006 Cardiovascular endothelins: essential regulators of cardiovascular homeostasis. Pharmacol Ther 111:508–531 [PubMed]
  • Agapitov AV, Haynes WG 2002 Role of endothelin in cardiovascular disease. J Renin Angiotensin Aldosterone Syst 3:1–15 [PubMed]
  • Schubert R, Lidington D, Bolz SS 2008 The emerging role of Ca2+ sensitivity regulation in promoting myogenic vasoconstriction. Cardiovasc Res 77:8–18 [PubMed]
  • Russo I, Del Mese P, Doronzo G, Mattiello L, Viretto M, Bosia A, Anfossi G, Trovati M 2008 Resistance to the nitric oxide/cyclic guanosine 5′-monophosphate/protein kinase G pathway in vascular smooth muscle cells from the obese Zucker rat, a classical animal model of insulin resistance: role of oxidative stress. Endocrinology 149:1480–1489 [PubMed]
  • Pacher P, Beckman JS, Liaudet L 2007 Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424 [PMC free article] [PubMed]
  • Guillot PV, Guan J, Liu L, Kuivenhoven JA, Rosenberg RD, Sessa WC, Aird WC 1999 A vascular bed-specific pathway. J Clin Invest 103:799–805 [PMC free article] [PubMed]

Articles from Endocrine Reviews are provided here courtesy of The Endocrine Society

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Compound
    PubChem Compound links
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...