Colonic blood flow responses in experimental colitis: time course and underlying mechanisms

Abstract

Human inflammatory bowel diseases (IBD) are associated with significant alterations in intestinal blood flow, the direction and magnitude of which change with disease progression. The objectives of this study were to determine the time course of changes in colonic blood perfusion that occur during the development of dextran-sodium-sulfate (DSS)-induced colonic inflammation and to address the mechanisms that may underlie these changes in blood flow. Intravital microscopy was used to quantify blood flow (from measurements of vessel diameter and red blood cell velocity) in different-sized submucosal arterioles of control and inflamed colons in wild-type (WT) mice. A significant (18–30%) reduction in blood flow was noted in the smallest arterioles (<40 μm diameter) on days 4–6 of DSS colitis. The arteriolar responses to bradykinin in control and DSS-treated WT mice revealed an impaired endothelium-dependent, but not endothelium-independent, vasodilation in the inflamed colon. However, this impaired vasodilatory response to bradykinin after DSS treatment was not evident in mutant mice that overexpress Cu,Zn-superoxide dismutase. Rescue of the bradykinin-induced vasodilation during DSS colitis was also observed in mice that are genetically deficient in the NAD(P)H oxidase subunit gp91phox. These findings indicate that the decline in blood flow during experimental colitis may result from a diminished capacity of colonic arterioles to respond to endogenous endothelium-dependent vasodilators like bradykinin and that NAD(P)H oxidase-derived superoxide plays a major role in the induction of the inflammation-induced endothelium-dependent arteriolar dysfunction.

An angiotensin II receptor antagonist reduces inflammatory parameters in two models of colitis

“…As mentioned before many cells in the colon express Ang II receptors, including those on vascular endothelial cells, and the involvement of the microvascular system most likely plays an important role. Although this study did not investigate changes in microcirculation related with the colitis, we and others have previously demonstrated the importance of blood flow and microvascular changes to progression of the colitis in the TNBS animal model [41,42]. Treatment with Losartan has been shown to attenuate leukocyte recruitment following ischemia-reperfusion injury in the intestine and suggests the contribution of the Ang II receptors to the inflammatory state [43].…”

Multiple Pathogenic Roles of Microvasculature in Inflammatory Bowel Disease: A Jack of All Trades

“…Another study demonstrates the diminished capacity of colonic arterioles to respond to endogenous endothelium-dependent vasodilators like bradykinin and shows that NAD(P)H oxidase-derived superoxide plays an important role in the inflammation-induced arteriolar dysfunction. 76 In addition, the fibrinoid occlusions appearing in CD-involved intestine have a histological appearance characteristic of prolonged disruption in the local vascular supply leading to microinfarction. 77 Taken together, these studies suggest that the microvascular anatomy undergoes vascular remodeling resulting in hypoperfused and ischemic/hypoxic environment in the gut, which possibly results in tissue necrosis.…”

Loss of purinergic vascular regulation in the colon during colitis is associated with upregulation of CD39

“…and animal models of IBD have revealed alterations in gastrointestinal (GI) blood flow (2,15,22,26) and angiogenesis (4 -6). These changes may contribute to disease pathogenesis, inasmuch as defects in mucosal perfusion render the mucosal barrier susceptible to breakdown.…”

“…These data implicate upregulation of CD39 in impaired sympathetic regulation of gastrointestinal blood flow during colitis. purinergic neurotransmission; ectonucleotidase; inflammation; sympathetic; vasoconstriction STUDIES OF PATIENTS WITH INFLAMMATORY bowel disease (IBD) and animal models of IBD have revealed alterations in gastrointestinal (GI) blood flow (2,15,22,26) and angiogenesis (4 -6). These changes may contribute to disease pathogenesis, inasmuch as defects in mucosal perfusion render the mucosal barrier susceptible to breakdown.…”