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NEUROREGULATION AND MOTILITY

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

Departments of Physiology and Medicine, Gastrointestinal Diseases Research Unit and Centre for Neuroscience Studies, Queen's University, Kingston, Ontario, Canada

Submitted 22 July 2008 ; accepted in final form 8 December 2008

Evidence from patients with inflammatory bowel disease (IBD) and animal models suggests that inflammation alters blood flow to the mucosa, which precipitates mucosal barrier dysfunction. Impaired purinergic sympathetic regulation of submucosal arterioles, the resistance vessels of the splanchnic vasculature, is one of the defects identified during IBD and in mouse models of IBD. We hypothesized that this may be a consequence of upregulated catabolism of ATP during colitis. In vivo and in vitro video microscopy techniques were employed to measure the effects of purinergic agonists and inhibitors of CD39, an enzyme responsible for extracellular ATP catabolism, on the diameter of colonic submucosal arterioles from control mice and mice with dextran sodium sulfate [DSS, 5% (wt/vol)] colitis. Using a luciferase-based ATP assay, we examined the degradation of ATP and utilized real-time PCR, Western blotting, and immunohistochemistry to examine the expression and localization of CD39 during colitis. Arterioles from mice with DSS colitis did not constrict in response to ATP (10 µM) but did constrict in the presence of its nonhydrolyzable analog ,β-methylene ATP (1 µM). ,β-Methylene ADP (100 µM), an inhibitor of CD39, restored ATP-induced vasoconstriction in arterioles from mice with DSS-induced colitis. CD39 protein and mRNA expression was markedly increased during colitis. Immunohistochemical analysis demonstrated that, in addition to vascular CD39, F4/80-immunoreactive macrophages accounted for a large proportion of submucosal CD39 staining during colitis. These data implicate upregulation of CD39 in impaired sympathetic regulation of gastrointestinal blood flow during colitis.

purinergic neurotransmission; ectonucleotidase; inflammation; sympathetic; vasoconstriction

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				From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease PNAS, September 29, 2009; 106(39): 16788 - 16793.

				M. A. Motagally, S. Neshat, and A. E. Lomax Inhibition of sympathetic N-type voltage-gated Ca2+ current underlies the reduction in norepinephrine release during colitis Am J Physiol Gastrointest Liver Physiol, May 1, 2009; 296(5): G1077 - G1084. [Abstract] [Full Text] [PDF]