VEGF-A Links Angiogenesis and Inflammation in Inflammatory Bowel Disease Pathogenesis

Franco Scaldaferri, Stefania Vetrano, Miquel Sans, Vincenzo Arena, Giuseppe Straface, Egidio Stigliano, Alessandro Repici, Andreas Sturm, Alberto Malesci, Julian Panes, Seppo Yla-Herttuala, Claudio Fiocchi, Silvio Danese

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Abstract

Background & Aims: 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.

Original languageEnglish
JournalGastroenterology
Volume136
Issue number2
DOIs
Publication statusPublished - Feb 2009

ASJC Scopus subject areas

  • Gastroenterology

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    Scaldaferri, F., Vetrano, S., Sans, M., Arena, V., Straface, G., Stigliano, E., Repici, A., Sturm, A., Malesci, A., Panes, J., Yla-Herttuala, S., Fiocchi, C., & Danese, S. (2009). VEGF-A Links Angiogenesis and Inflammation in Inflammatory Bowel Disease Pathogenesis. Gastroenterology, 136(2). https://doi.org/10.1053/j.gastro.2008.09.064