Arteriolar and Capillary Alterations Associated with IBD

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Blood Flow

The resting tone of arterioles appears to result from a complex interaction of metabolic, myogenic, neurohumoral, and physical (e.g., stretch or shear) signals received by the

Figure 2 All segments of the microcirculation contribute to the pathophysiology of chronic gut inflammation. A variety of inflammatory mediators (e.g., histamine, bradykinin, nitric oxide, prostaglandins) produced by the affected tissue relax the vascular smooth muscle surrounding arterioles. The consequent dilation of arterioles leads to an increased blood flow (hyperemia), thereby producing erythema. Another consequence of arteriolar dilation is an increased hydrostatic pressure in the downstream capillaries. The increased capillary hydrostatic pressure alters the balance of forces that govern fluid movement across intestinal capillaries to favor net fluid filtration. The increased capillary filtration rate contributes to the interstitial edema associated with gut inflammation. Proinflammatory cytokines (TNF, IFN-g, IL-12) released by activated mast cells, macrophages, and lymphocytes activate venular endothelial cells and increase expression of endothelial cell adhesion molecules that mediate leukocyte-endothelial cell adhesion and eventual emigration (tissue infiltration) of leukocytes. Leukocyte emigration is often associated with vascular protein leak (extravasation). Consequently, inflammation generally results in a diminished endothelial barrier function in venules that promotes the accumulation of albumin and other plasma proteins in the interstitium. The resultant increase in interstitial oncotic pressure further promotes fluid filtration across capillaries and accelerates the development of interstitial edema. (see color insert)

Figure 2 All segments of the microcirculation contribute to the pathophysiology of chronic gut inflammation. A variety of inflammatory mediators (e.g., histamine, bradykinin, nitric oxide, prostaglandins) produced by the affected tissue relax the vascular smooth muscle surrounding arterioles. The consequent dilation of arterioles leads to an increased blood flow (hyperemia), thereby producing erythema. Another consequence of arteriolar dilation is an increased hydrostatic pressure in the downstream capillaries. The increased capillary hydrostatic pressure alters the balance of forces that govern fluid movement across intestinal capillaries to favor net fluid filtration. The increased capillary filtration rate contributes to the interstitial edema associated with gut inflammation. Proinflammatory cytokines (TNF, IFN-g, IL-12) released by activated mast cells, macrophages, and lymphocytes activate venular endothelial cells and increase expression of endothelial cell adhesion molecules that mediate leukocyte-endothelial cell adhesion and eventual emigration (tissue infiltration) of leukocytes. Leukocyte emigration is often associated with vascular protein leak (extravasation). Consequently, inflammation generally results in a diminished endothelial barrier function in venules that promotes the accumulation of albumin and other plasma proteins in the interstitium. The resultant increase in interstitial oncotic pressure further promotes fluid filtration across capillaries and accelerates the development of interstitial edema. (see color insert)

blood vessel wall. Historically, the responses of arterioles to physiological stimuli were believed to be initiated almost exclusively by signals sensed by VSM cells. There is now clear evidence that endothelial cells play an important role in maintaining vascular tone by releasing substances (e.g., NO, prostacyclin) that modulate the delicate balance between vasodilation and vasoconstriction. An appreciation for the contribution of endothelial cells to vascular tone comes from studies demonstrating that acetylcholine dilates arterial smooth muscle only if the endothelium is intact and viable.

In active ulcerative colitis, the submucosal arteries display a convoluted course and dilatation and congestion of the mucosal and submucosal microvessels is often striking. Studies employing microangiography, vascular casts, and mesenteric angiography have demonstrated widened arteries and a rapid venous return, suggesting that an increase in colonic blood flow occurs with active ulcerative colitis. Another frequent vascular abnormality is vasodilation of the lymph node vasculature.

In Crohn's disease, the morphologic alterations are less uniform than those described for ulcerative colitis and the vascular changes show considerable variation from one patient to another. For example, angiographic examination of the small bowel in Crohn's disease indicates that the degree of dilation and engorgement of ileal and colonic microvessels may be as conspicuous as in active ulcerative colitis, although a reduced vascularity is also commonly reported. In addition, in areas with mild alteration (deep lymphocytic infiltration but not ulcerative lesions of fissures), there is a distinct focal hypervascularity in the sub-mucosa evidenced by numerous dilated arterial vessels that have a straight "broom-like" course [3]. Studies in patients with IBD indicate that blood flow in affected regions may increase two- to sixfold. In addition, determination of the intramural distribution of blood flow indicated that this increase is confined largely to the mucosal-submucosal layer. Based on these observations, Hulten and associates estimated that blood flow in the inflamed colon corresponds to 25 to 30 percent of the resting cardiac output and

Colonic Intramural Plexus

Arteriole

Figure 3 Microcirculatory pattern of the large and small intestinal mucosa. (A) Capillaries nearest the colonic mucosa are arranged in a honeycomblike plexus of interconnecting rings in which each ring of capillaries surrounds the openings of the colonic crypts. (B) Fountain-like pattern of blood flow to the small intestinal villus. The pattern of arterioles and venules conforms to the shape of the villus. This capillary plexus immediately underlies the base of the epithelium. (Figure adapted from Ref. [3].)

Arteriole

Figure 3 Microcirculatory pattern of the large and small intestinal mucosa. (A) Capillaries nearest the colonic mucosa are arranged in a honeycomblike plexus of interconnecting rings in which each ring of capillaries surrounds the openings of the colonic crypts. (B) Fountain-like pattern of blood flow to the small intestinal villus. The pattern of arterioles and venules conforms to the shape of the villus. This capillary plexus immediately underlies the base of the epithelium. (Figure adapted from Ref. [3].)

suggested that these high flows may represent an important factor contributing to the physical deterioration often observed in these patients [4]. In contrast to the results obtained in active and exudative stages of ulcerative colitis and Crohn's disease, colonic blood flow decreases below normal in the late fibrosing stage. A similar pattern is observed for the ileum in patients with Crohn's disease affecting this segment of the bowel. These findings correlate well with the observed reduction in vascularity in this stage of disease progression. In addition to these changes, a characteristic distention or clubbing of the villi occurs and, in a later phase, epithelial denudation and destruction of the villi. Although the mechanisms underlying these alterations in colonic blood flow are unknown, sustained overproduction of NO and/or arachidonic acid metabolites may be important.

Arteriolar-Dependent Mechanisms of Interstitial Edema in IBD

Interstitial edema and mucosal exudation are cardinal histopathological signs of inflammatory bowel disease. All three segments of the intestinal microvasculature, that is, arterioles, capillaries, and venules, contribute to the interstitial edema associated with IBD. The arteriolar dilation that accounts for the intense hyperemia during inflammation may represent a major pathway for enhanced filtration of fluid across the walls of downstream capillaries. This arteriole dilation-dependent enhancement of capillary fluid filtration results from an increased capillary hydrostatic pressure. Capillary pressure (Pc) rises when arterioles dilate because a larger fraction of the prevailing arterial pressure is transmitted to the downstream capillaries. An elevated Pc alters the balance of hydrostatic and oncotic forces that govern fluid movement across capillaries. If the increment in Pc is of sufficient magnitude, the rate of fluid filtration is accelerated to an extent that produces interstitial edema, that is, the rate of fluid entry into the mucosal or submucosal interstitium exceeds the capacity of lymphatics to drain the interstitial compartment. That capillary filtration is elevated in the intestinal vasculature during IBD is supported by reports describing increased intestinal lymph flow. Although the magnitude of the increase in Pc during IBD has not been determined experimentally, published reports of blood flow changes in human subjects provide some insights into this potential Pc elevation during the inflammatory response.

Angiographic studies in patients with ulcerative colitis or Crohn's disease demonstrate widened splanchnic arteries. However, estimates of colonic blood flow (using an isotope washout technique) in patients with inflammatory bowel disorders indicate a two- to sixfold increase in colon blood flow that is largely confined to the mucosal-submucosa layers [5]. As mentioned previously, Hulten and associates have estimated that the inflamed colon, in the early "exudative" stage, may be supplied by approximately 1,500 mL/ min of blood, corresponding to 25 to 30 percent of the resting cardiac output [4]. Assuming that the decrease in colonic vascular resistance occurs predominately at the arteriolar level, it can be estimated that microvascular pressure may rise by 10 to 40mmHg. An increase in capillary pressure of this magnitude should profoundly increase the rate of capillary fluid filtration and promote a massive accumulation of interstitial fluid. Similarly, the fluid filtration that results from such a large increase in Pc should lead to disruption of the mucosal barrier and exudation of interstitial fluid into the lumen.

Angiogenesis

The intestinal vascular beds have only a small fraction (e.g., 20-30%) of the total capillary population open for blood perfusion. Physiologic stresses such as an increased metabolic demand and/or reduced blood flow in these tissues are generally associated with the recruitment of additional perfused capillaries. Consequently, the classic concept has been that alterations in functional capillary density allow for local modulation of O2 exchange area and capillary-to-cell diffusion distances.

Capillary proliferation (e.g., angiogenesis) represents a potential mechanism whereby tissues can compensate for chronic alterations in oxygen delivery and/or metabolic demand, and to restore organ function after injury. The endothelium that lines normal capillaries is an extremely stable population of cells with very low mitotic activity; only 0.01 percent of endothelial cells in the body are dividing at any given time. Hence, capillary growth and proliferation is rarely observed in normal adult tissues except during wound healing and cyclical events in the female reproductive cycle (ovulation, menstruation). In the presence of appropriate stimuli, the process of angiogenesis (development of new blood vessels from an existing vascular network) can be initiated. Endothelial cells exposed to such stimuli first release proteases that degrade the underlying basement membrane and surrounding structural elements [6]. The cells then migrate toward the angiogenic (chemotactic) stimulus within the extravascular space, with a concomitant proliferation of the endothelial cells lining the vessel wall to replace the previously migrated cells. The migrating and proliferating endothelial cells form cordlike structures in target tissues that later canalize to functional vessels, which are further stabilized by surrounding pericytes. The initiation of angiogenesis is often associated with an increased capillary permeability that serves to enrich the adjacent interstitial compartment with plasma components. The role of angiogenesis in IBD is, at present, unclear.

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