4th Annual BMRP Investigator Meeting - Abstract

Angiogenesis as a Novel Component in the Pathogenesis of Inflammatory Bowel Disease

Franco Scaldaferri, Cristina Graziani, Marco Marini, Antonio Gasbarrini and Silvio Danese^a

Department of Internal Medicine, Catholic University of Rome (Italy)

We investigated angiogenesis in Crohn’s disease (CD) and ulcerative colitis (UC) by quantifying the mucosal vascularization state, assessing local expression of the angiogenic marker αvβ3 and exploring the presence of functional pro-angiogenic activity of inflammatory bowel disease (IBD) tissue.  In vivo levels of the key pro-angiogenic molecules IL-8, bFGF and VEGF and their cellular source(s) were examined.  Whether they could promote angiogenesis in vitro also was tested with human intestinal microvascular endothelial cells (HIMEC).

Microvessel density was significantly (p<0.05) higher in CD and UC compared to control mucosa.  αvβ3 was only sporadically detected in normal mucosa, but was ubiquitously expressed on IBD vessels as revealed by co-localization with CD31.  bFGF and TNF-α, but not VEGF, markedly upregulated αvβ3 expression in HIMEC.  IBD extracts increased vascularization in chick embryos to the same extent as VEGF.  Both CD and UC extracts dose-dependently induced HIMEC migration to a significantly (p<0.05) greater degree than controls, a phenomenon primarily dependent on IL-8, and less on bFGF or VEGF, as shown by antibody neutralization studies.

Compared to controls, IL-8 levels in IBD extracts were remarkably (p<0.01) higher in UC and CD, and the same was true for bFGF.  VEGF showed a three-fold increased in IBD compared to normal mucosa.  Unstimulated HIF produced negligible amounts of IL-8, but low and high amounts of bFGF and VEGF, respectively.  After TNF-α stimulation, production of IL-8 and VEGF increased dramatically, while that of bFGF remained unchanged.  In contrast, LPMC spontaneously produced large amounts of all three mediators, and these increased with LPS and anti-CD3 stimulation for IL-8, while only LPS enhanced bFGF and VEGF.  Both CD and UC extracts induced a four-fold increase in HIMEC migration, which was inhibited primarily by blocking IL-8, but less bFGF and VEGF.

Based on morphological and functional evidence of pro-angiogenic activity in CD and UC mucosa, it appears that the mucosal microvasculature in IBD undergoes an intense process of angiogenesis.  This suggests that angiogenesis is a vital component of IBD pathogenesis and provides the material and conceptual bases for considering anti-angiogenic strategies for IBD therapy, as currently being tested in other autoimmune disorders.

^aPrincipal Investigator