Novel Mechanism of Vasodilation in Inflammatory Bowel Disease

Abstract

Objective-Endothelium-dependent dilation to acetylcholine (Ach) is reduced in mucosal arterioles from patients with inflammatory bowel disease (IBD). The contributions of both nitric oxide (NO) and endothelial-derived hyperpolarizing factor (EDHF) are decreased. We hypothesized that the remaining dilation results from products of cyclooxygenase. Methods and Results-High-performance liquid chromatography (HPLC) was used to isolate eicosanoid vasodilator products and videomicroscopy was used to examine vasomotor responses in human mucosal arterioles from subjects with or without IBD undergoing bowel resection surgeries. In subjects without IBD, Ach constricted (Ϫ52%Ϯ10%) arterioles devoid of endothelium. Indomethacin (INDO) (cyclooxygenase inhibitor) had no effect. In contrast, Ach dose-dependently dilated both intact and endothelial denuded arterioles from patients with IBD. The dilation was converted to constriction by INDO (Ϫ54%Ϯ9%; PϽ0.05 versus non-IBD) or by BWA868C (PGD 2 receptor antagonist). Only in arterioles from subjects with IBD did Ach produce an arachidonic acid metabolite that comigrated on HPLC with PG D 2 (PGD 2 ). Exogenous PGD 2 dilated (maxϭ66%Ϯ4%) IBD arterioles. Conclusion-In arterioles from IBD patients, Ach-mediated dilation shifts from endothelial production of NO and EDHF to nonendothelial generation of a PG, likely PGD 2 . This is a novel dilator mechanism arising from nonendothelial vascular tissue that compensates for loss of endothelium-dependent dilation. PGD 2 appears to be important in regulating mucosal blood flow in patients with IBD, implicating potentially detrimental effects from nonsteroidal antiinflammatory drugs. Key Words: cyclooxygenase Ⅲ inflammatory bowel disease Ⅲ microcirculation Ⅲ prostaglandin Ⅲ vasodilation E ndothelium-dependent vasorelaxation plays a critical role in regulating tissue perfusion. 1 Impaired vasorelaxation is a key feature of microvascular dysfunction that contributes to the pathophysiology of diabetes mellitus, hyperlipidemia, and atherosclerosis. 2,3 A new association of microvascular dysfunction with clinical inflammatory bowel disease (IBD) (Crohn disease, ulcerative colitis) has been made. 4 IBD is characterized by refractory, poorly healing mucosal ulcerations, and impaired endothelium-mediated vasorelaxation. 4,5 Using in vitro dimension measurements of cannulated 50 to 200 m arterioles, we have demonstrated that normal intestinal microvessels dilate in response to the classic endothelium-dependent agonist, acetylcholine (Ach). 4 After inhibiting nitric oxide (NO) synthase, cyclooxygenase (COX), and hyperpolarization mechanisms, or after endothelial denudation, constriction was observed. Microvessels isolated from chronically inflamed IBD tissue demonstrated loss of NO-mediated and hyperpolarization-mediated vasodilation in response to Ach. However, in contrast to vessels from subjects without IBD or from uninvolved segments of bowel from patients with IBD, arterioles from active IBD segments had attenuated dilation to Ach that was independ...

CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease

“…Immune system dysregulation is generally considered the major cause of IBD, but there is a growing appreciation for the role of the vasculature in modifying this response (17)(18)(19). CD39 is both the dominant immune cell and vascular ectonucleotidase, so its protective effect against DSS colitis in mice may be due to either of these two roles, or perhaps both.…”

The Human Microcirculation

“…Microvascular dysfunction contributes to inflammation in visceral fat, which may explain the associated elevation in cardiovascular risk in subjects with excess visceral adiposity 31 . Microcirculatory dysfunction contributes etiologically or has a primary association with a myriad of diseases including obstructive sleep apnea 32 , hypertrophic cardiomyopathy 10 , stress-related cardiomyopathy 33 , congestive heart failure with reduced ejection fraction 34 , idiopathic cardiomyopathy 35 , heart failure with preserved ejection fraction 36, 37 , inflammatory bowel disease 38, 39 , schizophrenia 40 , amyloidosis 41 , tobacco use 42 , aging 43 , systemic lupus erythematosus 44 , and even a sedentary life style 45 . Abnormalities in the microcirculation are responsible for no-reflow phenomenon (reviewed by Feher et al 46 ), damage from cardioplegic arrest 47 , coronary microvascular spasm 48 , cerebral vasospasm following subarachnoid hemorrhage 49 , and angiogenesis 50, 51 , including tumor angiogenesis 52 .…”

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