Tolstanova G. The biochemical mechanisms of inflammatory bowel disease pathogenesis

The study is dedicated to the investigation of the role of angiogenic factors in the inflammatory bowel disease (IBD) initiation and propagation. This is the first demonstration in different models of IBD that endothelial damage, increased colonic vascular permeability, epithelial hypoxia and upregulation of HIF-1 level precede epithelial barrier dysfunction, followed by erosions, ulceration and inflammation. Development of experimental colitis is associated with increased levels of transcription factor Egr-1, its binding to DNA and interaction with other transcription factors via Erk1/2-dependent mechanism. Transcription activity of Egr-1 does not depend on HIF-1. Egr-1 knockout mice have less severe colitis vs. wild type littermates. Acute and chronic stages of experimental IBD are characterized by increased of VEGF, VEGFR-1 and VEGFR-2 levels. Neutralizing anti-VEGF antibody significantly ameliorates experimental colitis in part by reducing excessive colonic vascular permeability and decreasing inflammatory cells infiltration. VEGF seems to mediate increased colonic vascular permeability in experimental IBD via the VEGFR-2/Src-dependent interaction of beta-arrestin2 with VE-cadherin. We found concomitant upregulation of VEGF, PDGF, MMP-9 and endostatin in IBD pathogensis. MMP-9 is a key enzyme to generate endostatin which may modulate the balance between VEGF and endostatin during experimental colitis. Endostatin plays an antagonistic role in VEGF-induced pathologic angiogenesis in IBD pathogenesis and VEGF-induced physiologic angiogenesis in duodenal ulcer pathogenesis.