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Granger DN, Senchenkova E. Inflammation and the Microcirculation. San Rafael (CA): Morgan & Claypool Life Sciences; 2010.

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Inflammation and the Microcirculation.

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Chapter 4Impaired Vasomotor Responses

4.1. Blood Flow Changes

Inflammation is associated with significant alterations in tissue blood flow, the direction and magnitude of which may change as the inflammatory response progresses. In the early phase of an inflammatory response, hyperemia is often noted, which likely accounts for the redness that has been used as a sign of inflamed tissue over the centuries. The hyperemic response probably reflects an initial reaction of arterioles to injury and to the rapid release of vasoactive mediators (histamine, bradykinin, neuropeptides, prostaglandins) produced by mast cells, macrophages, fibroblasts, parenchymal cells, and the vessel wall. The hyperemia has not been attributed to any single chemical mediator. Antihistamines and glucocorticoids have been shown to blunt inflammation-induced vasodilation. It has been proposed that the hyperemic response benefits the host because it helps to rid of (or dilute) the inciting agent and the increased blood flow facilitates the delivery of leukocytes to the site of inflammation [6265].

ECs may contribute to the early dilatory response of arterioles to inflammation by producing more NO, which relaxes VSM (Figure 4.1). The increased wall shear stress that results secondary to chemical mediator-induced dilation can elicit further vessel relaxation. Selective removal or destruction of the endothelium typically abolishes this response, suggesting the production and/or release of a VSM relaxing factor from EC. Increased shear stress has been shown to elicit a calcium-dependent activation of endothelial cell NO synthase, which oxidizes L-arginine to generate NO and L-citrulline. A role for NO in modulating arteriolar tone is supported by studies employing L-arginine analogs that inhibit NO synthase, as well as L-arginine supplementation to enhance NO production. Although NO has received the most attention as the endothelium-derived factor that mediates flow-dependent vasodilation, prostaglandins, hydrogen peroxide, hydrogen sulfide, and other vasoactive substances have also been implicated in this response [12,29,30,47,48,66,67].

FIGURE 4.1. Under control conditions, ECs respond to receptor-dependent dilators and shear stress by producing NO via calcium-calmodulin-dependent activation of nitric oxide synthase.


Under control conditions, ECs respond to receptor-dependent dilators and shear stress by producing NO via calcium-calmodulin-dependent activation of nitric oxide synthase. The NO diffuses into the underlying smooth muscle cell to activate guanylate cyclase, (more...)

Studies of the blood flow changes that accompany chronic inflammatory diseases suggest that the long-term steady-state response to inflammation is a reduction in tissue blood flow, rather than a hyperemia. In inflammatory bowel diseases (IBDs), for example, intestinal microvascular perfusion is increased during the fulminant (active) phase of the disease, while a reduction in flow is detected in chronically inflamed and remodeled intestine. While some animal models of IBD reveal a similar pattern of a transiently increased gut blood, followed by ischemia, other models exhibit relatively small changes in blood flow during the course of the inflammatory response. While the mechanism(s) that underlie the arteriolar dysfunction and decreased blood flow in the chronically inflamed bowel remain poorly defined, reduced responsiveness of arterioles to vasodilators and an enhanced sensitivity to vasoconstrictors have been offered as explanations [62,63,65,6872].

4.2. Endothelium-Dependent Vasodilation

Recent evidence implicates endothelial cell activation and a loss of NO-dependent dilation in the diminished blood flow that accompanies inflammation. While normal arterioles from human intestinal submucosa dilate in a dose-dependent and endothelium-dependent manner to acetylcholine, arterioles in the chronically inflamed intestine show a significantly reduced dilation response to acetylcholine. The inflamed arterioles exhibit an enhanced oxidative stress compared to control arterioles and treatment of arterioles from inflamed human intestine with a superoxide dismutase (SOD) mimetic restores the acetylcholine-induced vasodilatory response to a normal level (Figure 4.2A). The arterioles were also shown to be heavily dependent on cyclo-oxygenase (COX)-derived vasodilator products to maintain basal vascular tone and dilator capacity to acetylcholine. Overall, these findings in human IBD are consistent with a role for ROS-dependent impairment of the vasodilatory capacity of arterioles in the impaired tissue perfusion and oxygenation that occurs in chronically inflamed tissue [73].

FIGURE 4.2. Impaired endothelium-dependent vasodilation during intestinal inflammation in (A) humans with IBD and (B) in mice with dextran sodium sulfate (DSS)-induced colitis.


Impaired endothelium-dependent vasodilation during intestinal inflammation in (A) humans with IBD and (B) in mice with dextran sodium sulfate (DSS)-induced colitis. Control intestinal arterioles exhibit a brisk dilatory response to (A) acetylcholine and (more...)

The changes in blood flow and impaired arteriolar reactivity to endothelium-dependent vasodilators described in human IBD have been recapitulated in a widely employed mouse model of experimental colitis: dextran sodium sulfate (DSS). Both a significant reduction in blood flow and an impaired reactivity to bradykinin (an endothelium-dependent vasodilator) was noted in the smallest arterioles of wild type (WT) mice with DSS colitis (Figure 4.2B). However, the inflammation-induced vasomotor dysfunction was not evident in mutant mice that overexpress Cu,Zn-SOD and in mice that are genetically deficient in the NAD(P)H oxidase subunit gp91(phox). These findings support the involvement of superoxide in the impaired vasomotor response to inflammation and suggest that NAD(P)H oxidase is a major source of the ROS that mediates this vascular response [68].

A defective endothelium-dependent vasodilatory response has been described in many chronic pathologic conditions that include a significant inflammatory component such as atherosclerosis, diabetes, obesity, and hypertension. Similarly, both localized (ischemia–reperfusion [I/ R]) and systemic (sepsis) acute inflammatory responses also manifest the same vasomotor impairment. A role for ROS-mediated inactivation of NO has been implicated in the impaired endothelium-dependent dilation associated with all of these conditions. However, other inflammatory factors, including cytokines, C-reactive protein (CRP), and circulating oxidized low-density lipoprotein (oxLDL), have also been implicated in this response. Anti-inflammatory therapies, such as aspirin, statins, cytokine-directed antibodies, have been shown to improve endothelium-dependent vasodilation. While the effects of short-term exposure of resistance vessels to cytokines yield variable changes in tone, long-term exposure appears to enhance vessel responsiveness to constrictors (e.g., endothelin) and to impair endothelium-dependent vasodilation. Of the cytokines studied to date, TNF-α and IL-1β have received the most attention for their ability to impair endothelial cell and vasomotor functions. TNF-α may well exert its effects by enhancing superoxide formation via NADPH oxidase; however, there is also evidence that the cytokine impairs the stability of eNOS mRNA [66,67,7478].

Leukocytes can also exert a modulating influence on endothelium-dependent vascular reactivity. Various tissues exposed to I/R exhibit an impaired reactivity of small arteries and arterioles to acetylcholine and other endothelium-dependent vasodilators. It has been shown that animals receiving monoclonal antibodies against leukocyte adhesion molecules or that are genetically deficient in the same adhesion glycoproteins show an improved dilator response to acetylcholine after I/R, suggesting that leukocyte–endothelial cell adhesion contributes to the impaired vasomotor function. These observations, coupled with the protective actions of SOD treatment in the same models, suggest that adherent leukocytes, rather than ECs, may be the major source of superoxide that inactivates NO in this model of acute inflammation [51,79].

Copyright © 2010 by Morgan & Claypool Life Sciences.
Bookshelf ID: NBK53372
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