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Originally published online as doi:10.2353/ajpath.2008.080222 on July 3, 2008

Published online before print July 3, 2008
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(American Journal of Pathology. 2008;173:400-410.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080222

Substance P-Mediated Expression of the Pro-Angiogenic Factor CCN1 Modulates the Course of Colitis

Hon-Wai Koon*{dagger}, Dezheng Zhao*, Hua Xu*, Collin Bowe*{dagger}, Alan Moss*, Mary P. Moyer{ddagger} and Charalabos Pothoulakis*{dagger}

From the Gastrointestinal Neuropeptide Center,* Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; the Inflammatory Bowel Disease Center,{dagger} Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; and INCELL Corporation,{ddagger} San Antonio, Texas

Substance P (SP) regulates important intestinal functions, such as mucosal permeability, motility, chloride secretion, and inflammation via the neurokinin-1 receptor (NK-1R). Previous reports showed that vascularization and expression of angiogenic factors are evident in the colonic mucosa of rats with colitis and patients with inflammatory bowel disease. Here we determined whether SP is associated with angiogenesis. Human NCM460 colonocytes stably transfected with the human NK-1R (NCM460-NK-1R cells) and mice with dextran sodium sulfate-induced colitis were used. We found that expression of the angiogenic factor CCN1 was increased in the colons of patients with Crohn’s disease and ulcerative colitis. Mucosal extracts from inflammatory bowel disease patients induced human intestinal microvascular endothelial cell migration that was inhibited by blockade of CCN1 and its receptor integrin {alpha}vβ3. Both the degree of angiogenesis and CCN1 expression were elevated in the colons of mice with dextran sodium sulfate-induced colitis, which was reduced by treatment with the NK-1R antagonist CJ-12255. SP also increased CCN1 expression in NCM460-NK-1R colonocytes. SP exposure to human intestinal microvascular endothelial cells co-cultured with NCM460-NK-1R cells induced angiogenic activity that was inhibited by CCN1 silencing. In addition, intracolonic overexpression of CCN1 induced angiogenesis in mouse colon. Thus, SP mediates angiogenesis via CCN1 during colitis.






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Copyright © 2008 by the American Society for Investigative Pathology.