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Logo of jphysiolThe Journal of Physiology SiteMembershipSubmissionJ Physiol
J Physiol. Feb 1, 2005; 562(Pt 3): 647–653.
Published online Dec 16, 2004. doi:  10.1113/jphysiol.2004.079640
PMCID: PMC1665543

The microcirculation: a motor for the systemic inflammatory response and large vessel disease induced by hypercholesterolaemia?

Abstract

There is abundant evidence that links hypercholesterolaemia to both vascular inflammation and atherogenesis. While atherosclerosis is a large vessel disease that is characterized by leucocyte infiltration and lipid deposition in the wall of lesion-prone arteries, the inflammatory response does not appear to be confined to these locations. There is evidence supporting a systemic inflammatory response that is characterized by endothelial cell activation in multiple vascular beds and the appearance of activated immune cells and a wide range of inflammatory mediators in blood. The mechanism(s) responsible for initiating this systemic response remain poorly defined, although several inciting factors have been proposed, including infectious agents and oxidative stress resulting from one or more of the cardiovascular risk factors (e.g. hypercholesterolaemia, hypertension). While cells within lesion-prone arteries are often inferred as the source of circulating inflammatory mediators during atherogenesis, the fact that endothelial cells throughout the vasculature are activated raises the possibility that the microvasculature (which encompasses a vast endothelial surface area) may contribute to creating the systemic inflammatory milieu that is linked to atherogenesis. This review addresses evidence that links the microvasculature to the inflammatory responses induced by hypercholesterolaemia and offers the hypothesis that inflammatory events initiated within the microcirculation may contribute to initiation and/or progression of large vessel disease.

Since vascular diseases are responsible for the majority of disabilities and deaths in Western society, much attention has been devoted to defining the mechanisms that underlie these disease processes. Recently, inflammation has been recognized as a link between cardiovascular risk factors and the vessel dysfunction/injury associated with several vascular diseases. This is particularly evident in atherosclerosis, a progressive disease characterized by the accumulation of lipids in large arteries, wherein elevated blood levels of inflammatory mediators (e.g. tumour necrosis factor (TNF)-α, interleukin (IL)-6) and surrogate markers of inflammation (e.g. soluble vascular cell adhesion molecule-1 (VCAM-1), C-reactive protein (CRP)) have been proposed as gauges of atherosclerotic risk. It is generally held that the activation of endothelial cells in atheroma-prone arteries results in the development of an inflammatory focus that can facilitate the deposition of more lipids, promote plaque rupture, and elicit the formation of a thrombus. However, the endothelial cell activation associated with atherosclerosis and hypercholesterolaemia (the dominant risk factor associated with this disease) does not appear to be confined to atheroma-bearing large arteries. Regions of the macro- and microvasculature that are not associated with overt lesion development also assume an inflammatory phenotype characterized by oxidative stress and endothelial cell activation. In hypercholesterolaemic animals, the elevated systemic markers of inflammation, the impaired dilatory capacity of arterioles, and the increased blood cell recruitment in postcapillary venules appear to be linked (either directly or indirectly) to endothelial cell activation and are observed long before lesion development in large arteries.

The inflammatory profile associated with atherogenesis

The ongoing inflammatory process that is associated with atherosclerosis is manifested by activation of vascular endothelial cells and circulating blood cells, and an increased plasma concentration of inflammatory mediators. The frequency and intensity of these changes during atherosclerosis have led to the proposal that endothelial dysfunction (impaired flow-mediated vasodilatation, circulating soluble endothelial cell adhesion molecules (CAMs)) and blood levels of inflammatory mediators, such as CRP, should be used clinically as screening tools for this disease (Naghavi et al. 2003). These manifestations of endothelial dysfunction appear to be linked to oxidative stress and an imbalance between superoxide and nitric oxide (NO) in vascular endothelial cells. The endothelial oxidative stress (which is reflected systemically by elevated blood levels of F-2 isoprostane, a product of lipid peroxidation) is largely due to activation of superoxide-producing NAD(P)H oxidase in arteries. Interestingly, many factors that have been implicated in atherosclerosis, including the rennin–angiotensin system and cytokines (interferon-γ (IFN-γ)) may stimulate this pathway via the upregulation of NAD(P)H oxidase subunits etc (Wassmann et al. 2004). The oxidative stress, impaired endothelium-dependent vasodilatation, and increased endothelial CAM expression are not confined to lesion-prone arteries, suggesting that factors other than endothelial activation (e.g. mechanical forces) may prime specific regions of large arteries for plaque formation.

The increased endothelial CAM expression during atherogenesis not only provides a number of surrogate markers of endothelial cell activation (i.e. circulating soluble CAMs) (Meydani, 2003), but also mediates a critical step in atherosclerotic lesion formation, i.e. the recruitment of leucocytes into the artery wall (Nageh et al. 1997). In parallel, the activation state of circulating leucocytes is also elevated, leading to higher expression/affinity of their adhesion glycoproteins. Circulating platelets are also activated during atherogenesis. These activated platelets appear to favour the recruitment of leucocytes onto endothelial cells overlying plaques by forming platelet–monocyte aggregates and by depositing chemokines (e.g. regulated on activation normal T cell expressed and secreted (RANTES) and platelet factor-4 (PF-4)) onto monocytes and endothelial cells; events that are dependent on platelet-associated P-selectin (Huo et al. 2003).

The profile of cytokines (IL-6, TNF-α), chemokines (monocyte chemoattractant protein (MCP-1)), and other substances (CRP, CD40 ligand (CD40L)) that accumulate in blood during atherogenesis is consistent with an inflammatory response. A role for some of these agents (e.g. IL-6, CRP) in the pathogenesis of human atherosclerosis is suggested by significant correlations with the onset and/or severity of coronary and peripheral atherosclerosis (Rattazzi et al. 2003). However, mice that are genetically deficient in certain cytokines (e.g. IFN-γ, IL-12, IL-18) exhibit a blunted atherosclerotic response to hypercholesterolaemia (Gupta et al. 1997; Davenport & Tipping, 2003; Elhage et al. 2003), even though circulating levels of these cytokines are not elevated during atherosclerosis, suggesting that the blood profile of inflammatory mediators that accompanies atherogenesis does not adequately reflect the array of factors contributing to this disease process. It is noteworthy that some of these cytokines (e.g. IFN-γ) can induce the impaired endothelium-dependent vasodilatation that results from hypercholesterolaemia (Stokes & Granger, 2004). While the cellular sources of these pro-atherogenic inflammatory mediators remain unclear, as does the contribution of lesion-prone versus lesion-resistant segments of the vascular tree to mediator production/release, it is plausible that the activated endothelial cells directly and/or indirectly contribute to the generation of these mediators. Nonetheless, the inciting factors for the endothelial cell activation and accompanying inflammatory environment in atherosclerosis remain unclear.

Infectious agents (bacteria and viruses) have received considerable attention as potential inciting factors for the systemic inflammatory response that accompanies atherogenesis. Cytomegalovirus, Chlamydia pneumonia, and Porphyromonas gingivalis infect a large percentage of humans and are found in atherosclerotic lesions. They infect and activate both endothelial cells and leucocytes, and infected vessels exhibit oxidative stress, increased adhesion molecule expression, and leucocyte–endothelial cell adhesion. A role for these microbes in atherogenesis is supported by studies where infected animals experience accelerated lesion development in large arteries (Streblow et al. 2001). In humans, titres for serum antibodies directed against agents such as Porphyromonas gingivalis appear to correlate with blood levels of certain surrogate markers of inflammation that have been proposed as gauges of atherosclerotic risk (e.g. CRP) (Craig et al. 2003). Impaired endothelium-dependent vasodilatation in non-lesion-prone arteries also accompanies infection with cytomegalovirus (Grahame-Clarke et al. 2003) or Porphyromonas gingivalis. However, definitive proof that infection of the vessel wall and/or circulating immune cells is sufficient to initiate atherosclerosis is lacking.

Other plausible initiators of the endothelial cell activation and inflammation associated with atherogenesis are the established risk factors for cardiovascular disease, including elevated low-density lipoprotein (LDL) cholesterol, hypertension and diabetes-associated hyperglycaemia, all of which promote endothelial activation. Redox-sensitive gene expression appears to link the observed endothelial oxidative stress to enhanced production of inflammatory mediators, some of which are elevated in the blood and may act in concert with local signalling events triggered within vascular endothelium. This may explain why such risk factors appear to ‘prime’ both the vascular endothelium and circulating immune cells to respond in an exaggerated manner to additional inflammatory stimuli (Granger, 1999).

While the relative importance of the established cardiovascular risk factors, infectious agents and other genetic and environmental factors to the induction of atherosclerotic disease remains poorly understood, it is evident that there is an abundance of potential inciting factors that may induce the phenotypic changes in endothelial and immune cells during atherogenesis. However, it remains unclear whether lesion-prone arteries and atherosclerotic lesions per se represent the sole sites of endothelial cell and immune cell activation that drive this disease process. In the following sections, consideration is given to the potential roles of both lesion-prone arteries (that develop plaques) and the microvasculature as motors for the inflammatory responses that accompany the development of atherosclerosis.

Atheromas: a site of inflammation and source of systemic inflammatory mediators in atherogenesis

There is a large body of evidence that supports the existence of an intense inflammatory response in atheromas (Libby, 2002). Soon after the induction of hypercholesterolaemia, there is evidence for endothelial cell activation, the expression of CAMs on the surface of endothelial cells, and the release of soluble endothelial CAM isoforms into the circulation. A consequence of these changes in lesion-prone arteries is the attachment of leucocytes to the endothelial cell surface and subsequent infiltration of these leucocytes into the intimal layer of the arterial wall. The accumulation of a variety of leucocyte populations (macrophages, mast cells, T-lymphocytes) into this vessel compartment produces an inflammatory focus that favours the deposition of lipids and that is characterized by an oxidative stress and the generation of a variety of pro-inflammatory cytokines and chemokines, which further activate the endothelial cells to recruit additional inflammatory cells, thereby sustaining or intensifying the inflammatory milieu. If these inflammatory conditions within the arterial wall prevail and risk factors such as hypercholesterolaemia persist, the lipid deposit grows and the plaque becomes vulnerable to rupture.

While it is generally assumed that there is an enhanced production and release of reactive oxygen species, cytokines, chemokines and other inflammatory mediators within atherosclerotic plaques and that these mediators act via autocrine and paracrine mechanisms to elicit and sustain the local intramural inflammatory response, there is also evidence for the potential release of the same mediators into the circulation where they can induce a systemic inflammatory response and be used as surrogate markers of atherosclerotic disease. Indeed, several products of endothelial cell and leucocyte activation in plaques appear to correlate with the progression of the atherosclerotic lesion development. For example, circulating TNF-α levels have been reported to be proportional to intimal thickness and the degree of early atherosclerosis (Skoog et al. 2002). Similarly, blood levels of several products of endothelial cell activation, including soluble endothelial CAMs, endothelin-1 and von Willebrand factor, are increased during atherosclerosis and correlate with the extent of atherosclerosis in coronary artery disease (Lerman et al. 1991; Blann et al. 1997; Meydani et al. 2003).

CRP, an acute phase protein that appears to be a particularly robust marker of atherosclerotic risk, is produced by the liver in response to inflammatory cytokines, such as IL-6. Since IL-6 is produced within atherosclerotic lesions, and the blood levels of this cytokine are elevated during atherogenesis, it might be expected that plaque-derived IL-6 stimulates the liver to produce the CRP detected in individuals at cardiovascular risk. It is plausible therefore that several mediators of inflammation generated within atherosclerotic lesions may gain access to the blood circulation where they can exert an influence on endothelial cells in other regions of vascular system, including other lesion-prone and lesion-resistant arteries, as well as the microvasculature.

Responses of the microcirculation during atherogenesis: insights gained from studies on hypercholesterolaemia

Studies on the responses of the microvasculature to elevated blood cholesterol levels have revealed changes that are consistent with endothelial cell activation in both arterioles and postcapillary venules of several vascular beds (Gauthier et al. 1995; Scalia et al. 1998; Nellore & Harris, 2002). These changes long predate the appearance of atherosclerotic plaques in large arteries. While the vascular dysfunction is manifested differently between arterioles and venules, an oxidative stress appears to be experienced by endothelial cells throughout the microvasculature. Consequently, reactive oxygen species signalling mechanisms and superoxide-mediated inactivation of NO are frequently implicated in the altered endothelial cell-dependent processes in the microcirculation that accompany hypercholesterolaemia (Harrison & Ohara, 1995).

In arterioles, the endothelial cell activation induced by hypercholesterolaemia is manifested as a diminished capacity for endothelium-dependent vasodilatation elicited by agents such as ACh that normally enhance NO production in endothelial cells. This NO stimulates cGMP generation in, and therefore relaxation, of adjacent smooth muscle cells. The magnitude of the impaired endothelium-dependent vasodilatation appears to be correlated with cholesterol levels, with detectable deficits noted even in the high normal range in humans (Steinberg et al. 1997), and is reversed by lipid-lowering strategies (Leung et al. 1993). Strategies to reduce oxidative stress, i.e. treatment with superoxide dismutase, supplementation of cofactors (tetrahydrobiopterin) and/or substrates for endothelial nitric oxide synthase, also ameliorate the arteriolar dysfunction (Kawashima & Yokoyama, 2004). Interestingly, studies with angiotensin II type-1 receptor (AT1-R) antagonists suggest that AT1-R activation on endothelial cells contributes to the oxidative stress and superoxide-mediated inactivation of NO experienced by these cells during hypercholesterolaemia. While there is substantial evidence linking the early endothelial cell dysfunction in arterioles to oxidative stress during hypercholesterolaemia, it remains unclear if and how the inflammatory and prothrombogenic milieu that accompanies the oxidative stress in downstream venules (discussed below) contributes to the defective arteriolar response to dilator stimuli. Reports describing an altered responsiveness of coronary microvessels to products of platelet activation support a role for platelets (Quillen et al. 1991), while studies demonstrating that cytokines, such as IFN-γ, TNF-α and IL-1, impair ACh-induced arterial dilatation suggest that such immune cell-derived products may also contribute to the arteriolar dysfunction in hypercholesterolaemia (De Kimpe et al. 1994; Kessler et al. 1997). A likely result of the defective endothelium (NO)-dependent vasodilator responses in hypercholesterolaemia is an impairment of blood flow regulation in different tissues.

Endothelial cell activation during hypercholesterolaemia is manifested differently in postcapillary venules, where these cells exhibit increased CAM expression that supports an elevated level of leucocyte and platelet adhesion. The hypercholesterolaemia-induced leucocyte adhesion is probably mediated by endothelial P-selectin, intercellular adhesion molecule-1 (ICAM-1) and VCAM-1, while platelet adhesion appears to be supported by P-selectin, which is also elevated on circulating platelets of hypercholesterolaemic humans and mice (Tailor & Granger, 2003). Roughly 80% of the adherent platelets observed in intestinal venules of hypercholesterolaemic mice are bound to adherent leucocytes, with the remaining 20% of platelets binding directly to venular endothelium. Furthermore, about half of the adherent leucocytes are bearing platelets (Tailor & Granger, 2004). It has been proposed that the adherent leucocytes not bearing platelets exhibit a lower activation state than those that do.

The hypercholesterolaemia-induced leucocyte and platelet recruitment in postcapillary venules appears to be linked to the oxidative stress experienced by these microvessels. Hypercholesterolaemic transgenic mice that overexpress CuZn-superoxide dismutase display attenuated leucocyte and platelet adhesion, implicating superoxide as a mediator of the inflammatory responses. NAD(P)H oxidase appears to be a major source of this superoxide because mice deficient in p47phox or gp91phox, subunits of NAD(P)H oxidase, demonstrate a similarly blunted blood cell recruitment response to hypercholesterolaemia (Stokes et al. 2001; Russell et al. 2004). Findings from bone marrow chimeric mice that are selectively deficient in p47phox in either the vessel wall or in circulating blood cells, suggest that both endothelial and blood cells (leucocyte and/or platelets) contribute to the NAD(P)H oxidase-mediated leucocyte adhesion in hypercholesterolaemic venules. This mechanism may explain the preferential binding of platelets to only some of the adherent leucocytes, which may achieve a higher state of activation and produce more superoxide via leucocyte-associated NAD(P)H oxidase.

It has been reported that venules respond to hypercholesterolaemia by decreasing the diameter of adjacent arterioles via an NO-dependent mechanism that ultimately leads to reduced capillary flow. The reduction in capillary and overall tissue perfusion also appears to be neutrophil dependent (Nellore & Harris, 2002). Indeed, neutrophils appear to be the dominant leucocyte population that binds to endothelium in postcapillary venules in the first 2 weeks after placing mice on a cholesterol-enriched diet (HCh) (Stokes et al. 2002). In addition, there is growing evidence that T-cells play a major indirect role in this venular inflammatory response (Stokes et al. 2003a, b). It has been shown that: (1) immunodeficient (SCID or RAG-1−/−) HCh mice exhibit a significantly attenuated inflammatory cell infiltration in postcapillary venules, compared with wild-type (WT)-HCh mice; (2) reconstitution of SCID-HCh or RAG-1−/− HCh mice with splenocytes (T-cells) from WT mice yields an inflammatory phenotype that is similar to WT-HCh mice; and (3) both CD4+ and CD8+ T-lymphocytes contribute to this hypercholesterolaemia-induced leucocyte recruitment in venules.

T-lymphocyte-derived IFN-γ also appears to contribute to the inflammatory phenotype in postcapillary venules of hypercholesterolaemic mice. IFN-γ−/− mice placed on a cholesterol-enriched diet do not exhibit the substantial leucocyte adherence and emigration seen in postcapillary venules of WT-HCh mice (Stokes et al. 2003a). Failure of splenocytes from IFN-γ−/− HCh mice to restore leucocyte adhesion in SCID-HCh mice, but the complete restoration of the inflammatory response when WT-HCh splenocytes are administered to IFN-γ−/−-HCh mice are consistent with lymphocytes being a major source of IFN-γ in hypercholesterolaemia. In addition, IFN-γ−/− HCh mice exhibit a significantly blunted oxidative stress in postcapillary venules, compared with their WT-HCh counterparts. This oxidant stress can be restored by administering WT-HCh splenocytes into IFN-γ−/−-HCh mice, implying that lymphocyte-derived IFN-γ is a key mediator of the oxidative stress in hypercholesterolaemic microvessels. This is consistent with the capacity of IFN-γ to activate oxidant-producing enzymes such as NAD(P)H oxidase. Interestingly, IL-12−/− mice (deficient in the p35 or p40 subunit) also respond to hypercholesterolaemia with an attenuated oxidative stress and leucocyte adhesion in postcapillary venules (Stokes et al. 2003b). Together, these findings are consistent with the possibility that IL-12 is critical for the induction of a Th1-type phenotype in T-lymphocytes, which leads to enhanced production of IFN-γ, ultimately eliciting the oxidative stress and blood cell–endothelial cell adhesive interactions that are observed in the hypercholesterolaemic microvasculature.

Contribution of the microvasculature to the systemic inflammatory milieu that drives atherogenesis

Whether or not the inflammatory events observed in the microvasculature during the initial days to months after the onset of hypercholesterolaemia are linked to the characteristic systemic inflammatory response and large vessel disease of atherogenesis remains unclear. Such a linkage may exist if mediators of inflammation generated within atherosclerotic lesions exert an influence on the microvasculature either directly, by engaging receptors on endothelial cells, or indirectly, by activating circulating leucocytes and platelets. However, this appears unlikely, at least during the early stages of atherogenesis, since the microvascular inflammation long predates significant leucocyte infiltration in lesion-prone arteries (Creager et al. 1990; Gauthier et al. 1995; Scalia et al. 1998; Nellore & Harris, 2002; Stokes et al. 2003a). Alternatively, the microcirculation may be an important source of the inflammatory signals that drive large vessel disease and it may contribute to the production of the circulating surrogate markers of inflammation that are detected in atherosclerotic patients (Rattazzi et al. 2003; Naghavi et al. 2004). The evidence for activation of endothelial cells, leucocytes and platelets in venules of several vascular beds, coupled to the involvement of immune cell-derived cytokines in the modulation of the microvascular responses to hypercholesterolaemia, supports the latter possibility.

If endothelial cell activation is indeed a rate-determining factor in producing the systemic inflammatory response to hypercholesterolaemia and if this inflammatory phenotype is assumed by endothelial cells throughout the vasculature, then any consideration of the relative contributions of endothelial cells in large arteries and the microvasculature to this response should take into account the endothelial surface area of each vascular compartment. Previously published estimates of the surface area of arterioles (261 337 cm2) and venules (879 989 cm2) in a 70-kg man suggest that these segments of the microvasculature, where endothelial cell activation is obvious during hypercholesterolaemia, provide an area for endothelial cell activation that is at least 300-times larger than the endothelial cell surface area (assuming 100% vessel involvement) associated with the atherosclerosis-prone aorta (156 cm2) and larger arteries (3333 cm2) (Wolinsky, 1980). While this huge difference in potential surface area for endothelial cell activation does not definitively implicate the microvasculature as the major source of the inflammatory mediators that drive the atherosclerotic process, it does suggest (based simply on the mass of tissue involved) that even a low-level inflammatory response elicited throughout the microvasculature by risk factors such as hypercholesterolaemia could result in the elevated blood levels of inflammatory mediators and surrogate markers of inflammation that are typically associated with atherosclerosis.

Figure 1 schematizes the mechanisms that may account for the participation of the microcirculation in atherogenesis. In the presence of risk factors for cardiovascular disease (e.g. hypercholesterolaemia), endothelial cells lining the microvasculature experience an oxidative stress and become activated. The resulting imbalance between superoxide and NO leads to impaired endothelium-dependent dilatation of arterioles and a diminished capacity to optimally maintain tissue perfusion. In venules, the oxidative stress and endothelial cell activation promotes the expression of adhesion molecules, leucocyte and platelet recruitment, and the subsequent generation of inflammatory mediators by blood and endothelial cells. These mediators as well as activated or ‘primed’ leucocytes and platelets gain access into venous blood and into the systemic circulation, where they can either prime, initiate or exacerbate an inflammatory response in those lesion-prone large arteries that are rendered vulnerable to oxidative stress and inflammation due to chronic exposure to flow disturbances (Davies et al. 2001). Working in concert with inflammatory processes initiated within the wall of lesion-prone arteries, the microcirculation-derived mediators and immune cells give rise to the nascent atheroma, which eventually evolves into the more complex atherosclerotic lesion.

Figure 1
Mechanism proposed to link early inflammatory events initiated in the microvasculature to the large vessel disease induced by hypercholesterolaemia

While the quantitative significance of the microvasculature to the overall atherogenic process remains uncertain, there is a clear need for more research on, and an improved understanding of, the inflammatory events that occur in the microcirculation in response to one or more risk factors for cardiovascular disease. The information resulting from this effort should provide novel and potentially useful insights into the inflammatory signals that drive large vessel disease. Furthermore, the information may be key to providing a better understanding of the mechanisms of production of the surrogate markers of inflammation that are gaining widespread acceptance for the identification of individuals who are at risk for development of cardiovascular disease.

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