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Am J Physiol Gastrointest Liver Physiol 295: G374-G381, 2008. First published June 26, 2008; doi:10.1152/ajpgi.90325.2008
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MUCOSAL BIOLOGY

A vascular endothelial growth factor mimetic accelerates gastric ulcer healing in an iNOS-dependent manner

Genevieve K. Dudar,1 Luca D. D'Andrea,2 Rossella Di Stasi,2 Carlo Pedone,2 and John L. Wallace1

1Inflammation Research Network, University of Calgary, Calgary, Alberta, Canada; and 2Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, Napoli, Italy

Submitted 5 May 2008 ; accepted in final form 20 June 2008

Angiogenesis is crucial to all types of wound healing, including gastric ulcer healing. The most potent promoter of angiogenesis is vascular endothelial growth factor (VEGF). We hypothesized that a 15-amino acid peptide designed to mimic the angiogenic action of VEGF would accelerate gastric ulcer healing. Gastric ulcers were induced in mice by serosal application of acetic acid. Treatment with the VEGF mimetic accelerated gastric ulcer healing when administered orally or intraperitoneally, at a dose of 50 ng/kg or greater. Such healing was not observed when the reverse sequence pentadecapeptide or the full-length VEGF protein was administered. Contrary to our hypothesis, the VEGF mimetic did not significantly increase angiogenesis in the ulcerated stomach. The enhancement of ulcer healing by the VEGF mimetic occurred independently of cyclooxygenase-2 (COX-2) activity but was blocked by inhibitors of inducible nitric oxide synthase (iNOS). These results demonstrate that a VEGF mimetic is a potent stimulus for gastric ulcer healing, even when given orally. The effects of the mimetic were independent of stimulatory effects on angiogenesis and COX-2 activity but were dependent on iNOS-derived NO production.

stomach; nitric oxide; cyclooxygenase; angiogenesis; prostaglandin; gastric mucosa


Address for reprint requests and other correspondence: J. Wallace, Dept. of Pharmacology & Therapeutics, Univ. of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, T2N 4N1, Canada (e-mail: wallacej{at}ucalgary.ca)






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