title: Substance P-mediated expression of the pro-angiogenic factor CCN1 modulates the course of colitis.
abstract: 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 alphavbeta3. 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.
authors.affiliation: Gastrointestinal Neuropeptide Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hon-Wai
authors.initials: HW
authors.lastname: Koon
authors.forename: Dezheng
authors.initials: D
authors.lastname: Zhao
authors.forename: Hua
authors.initials: H
authors.lastname: Xu
authors.forename: Collin
authors.initials: C
authors.lastname: Bowe
authors.forename: Alan
authors.initials: A
authors.lastname: Moss
authors.forename: Mary P
authors.initials: MP
authors.lastname: Moyer
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002465:Cell Movement; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000098:blood supply / Q000473:pathology; D003424:Crohn Disease / Q000378:metabolism / Q000473:pathology; D055515:Cysteine-Rich Protein 61; D016264:Dextran Sulfate; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000473:pathology / Q000503:physiopathology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013373:Substance P / Q000494:pharmacology / Q000502:physiology*
chemical_list: C480026:6-diphenylmethyl-5-(5-isopropyl-2-methoxybenzylamino)-1-azabicyclo(2.2.2)octane-3-carboxylic acid; D019086:Bridged Bicyclo Compounds, Heterocyclic; C501848:CCN1 protein, human; C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D017874:Immediate-Early Proteins; D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; D018040:Receptors, Neurokinin-1; D013373:Substance P; D016264:Dextran Sulfate