title: VEGF-A links angiogenesis and inflammation in inflammatory bowel disease pathogenesis.
abstract: OBJECTIVE
  Vascular endothelial growth factor A (VEGF-A) mediates angiogenesis and might also have a role in inflammation and immunity. We examined whether VEGF-A signaling has a role in inflammatory bowel disease (IBD).
  
  
  METHODS
  Expression levels of VEGF-A, and its receptors VEGFR-1 and VEGFR-2, were examined in samples from patients with IBD and compared with those of controls. The capacity of VEGF-A to induce angiogenesis was tested in human intestinal microvascular endothelial cells using cell-migration and matrigel tubule-formation assays. Levels of vascular cellular adhesion molecule-1 and intercellular adhesion molecule were measured by flow cytometry to determine induction of inflammation; neutrophil adhesion was also assayed. Expression patterns were determined in tissues from mice with dextran sulfate sodium (DSS)-induced colitis; the effects of VEGF-A overexpression and blockade were assessed in these mice by adenoviral transfer of VEGF-A and soluble VEGFR-1. Intestinal angiogenesis was measured by quantitative CD31 staining and leukocyte adhesion in vivo by intravital microscopy.
  
  
  RESULTS
  Levels of VEGF-A and VEGFR-2 increased in samples from patients with IBD and colitic mice. VEGF-A induced angiogenesis of human intestinal microvascular endothelial cells in vitro as well as an inflammatory phenotype and adherence of neutrophils to intestinal endothelium. Overexpression of VEGF-A in mice with DSS-induced colitis worsened their condition, whereas overexpression of soluble VEGFR-1 had the opposite effect. Furthermore, overexpression of VEGF-A increased mucosal angiogenesis and stimulated leukocyte adhesion in vivo.
  
  
  CONCLUSIONS
  VEGF-A appears to be a novel mediator of IBD by promoting intestinal angiogenesis and inflammation. Agents that block VEGF-A signaling might reduce intestinal inflammation in patients with IBD.
authors.affiliation: Division of Gastroenterology, Istituto Clinico Humanitas, University of Milan, Milan; Department of Internal Medicine, Catholic University, Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Scaldaferri
authors.forename: Stefania
authors.initials: S
authors.lastname: Vetrano
authors.forename: Miquel
authors.initials: M
authors.lastname: Sans
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Arena
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Straface
authors.forename: Egidio
authors.initials: E
authors.lastname: Stigliano
authors.forename: Alessandro
authors.initials: A
authors.lastname: Repici
authors.forename: Andreas
authors.initials: A
authors.lastname: Sturm
authors.forename: Alberto
authors.initials: A
authors.lastname: Malesci
authors.forename: Julian
authors.initials: J
authors.lastname: Panes
authors.forename: Seppo
authors.initials: S
authors.lastname: Yla-Herttuala
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiocchi
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D003092:Colitis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000503:physiopathology; D015212:Inflammatory Bowel Diseases / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2