title: Vascular endothelial growth factor receptor-2 inhibition in experimental murine colitis.
abstract: BACKGROUND
  In the setting of inflammatory bowel disease, inflammation is associated with a simultaneous increase in angiogenesis; moreover, elevated vascular endothelial growth factor (VEGF) levels implicate angiogenesis as a pathologic contributor to disease severity. We hypothesize that selectively inhibiting vascular endothelial growth factor receptor-2 (VEGFR2) in a model of murine colitis will reduce angiogenesis, resulting in decreased inflammation and disease severity, providing mechanistic insight into the role of pathologic angiogenesis in IBD.
  
  
  METHODS
  In a dextran sodium sulfate model of murine colitis, anti-VEGFR2 monoclonal antibody (DC101) or placebo was administered. Clinical assessments followed by histologic and molecular tissue analysis were performed to quantify inflammation, microvessel density (MVD), VEGF and VEGFR2 gene expression, and phosphorylated mitogen-activated protein kinase protein expression.
  
  
  RESULTS
  Weight loss began after d 6 with the treatment group demonstrating a more favorable percent weight change. Inflammation and MVD were similar between cohorts, both increasing in parallel toward a plateau. VEGF and VEGFR2 messenger RNA expression were not significantly different, but phosphorylated mitogen-activated protein kinase was elevated in the DC101 cohort (P = 0.03).
  
  
  CONCLUSIONS
  Despite a more favorable weight change profile in the treated group, no difference was observed between cohorts regarding clinical disease severity. However, a parallel rise in inflammation and MVD was observed coinciding with weight loss, suggesting their relationship in IBD. VEGFR2 downstream signaling was significantly elevated in the treated cohort, possibly by VEGF-independent signal transduction. Early and effective inhibition of angiogenesis by limiting downstream VEGF signaling or targeting multiple angiogenic pathways may block angiogenesis, thereby reducing disease severity and provide evidence toward the mechanism and clinical benefit of antiangiogenics in the setting of IBD.
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Knod
authors.forename: Eileen C
authors.initials: EC
authors.lastname: Donovan
authors.forename: Artur
authors.initials: A
authors.lastname: Chernoguz
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Crawford
authors.forename: Mary R
authors.initials: MR
authors.lastname: Dusing
authors.forename: Jason S
authors.initials: JS
authors.lastname: Frischer
mesh_terms: D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000187:drug effects / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; C511761:DC101 monoclonal antibody; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016264:Dextran Sulfate; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Colitis; Inflammatory bowel disease; VEGFR2