Endothelial caveolin-1 regulates pathologic angiogenesis in a mouse model of colitis.

Abstract

BACKGROUND & AIMS:

Increased vascular density has been associated with progression of human inflammatory bowel diseases (IBDs) and animal models of colitis. Pathologic angiogenesis in chronically inflamed tissues is mediated by several factors that are regulated at specialized lipid rafts known as caveolae. Caveolin-1 (Cav-1), the major structural protein of caveolae in endothelial cells, is involved in the regulation of angiogenesis, so we investigated its role in experimental colitis.

METHODS:

Colitis was induced by administration of dextran sodium sulfate to wild-type and Cav-1(-/-) mice, as well as Cav-1(-/-) mice that overexpress Cav-1 only in the endothelium. Colon tissues were analyzed by histologic analyses. Leukocyte recruitment was analyzed by intravital microscopy; angiogenesis was evaluated by immunohistochemistry and in vivo disk assays.

RESULTS:

Cav-1 protein levels increased after the induction of colitis in wild-type mice. In Cav-1(-/-) mice or mice given a Cav-1 inhibitory peptide, the colitis histopathology scores, vascular densities, and levels of inflammatory infiltrates decreased significantly compared with controls. Lower levels of leukocyte and platelet rolling and adhesion colitis also were observed in Cav-1(-/-) mice and mice given a Cav-1 inhibitory peptide, compared with controls. Cav-1(-/-) mice that received transplants of wild-type bone marrow had a lower colitis score than wild-type mice. Data from mice that overexpress Cav-1 only in the endothelium indicated that endothelial Cav-1 is the critical regulator of colitis. Genetic deletion or pharmacologic inhibition of endothelial Cav-1 also significantly decreased vascular densities and angiogenesis scores, compared with controls.

CONCLUSIONS:

Endothelial Cav-1 mediates angiogenesis in experimental colitis. Modulation of Cav-1 could provide a novel therapeutic target for IBD.

• Authors: John H Chidlow Jr, Joshua J M Greer, Christoph Anthoni, Pascal Bernatchez, Carlos Fernandez-Hernando, Carlos Fernadez-Hernando, Megan Bruce, Maisoun Abdelbaqi, Deepti Shukla, D Neil Granger, William C Sessa, Christopher G Kevil
• Journal: Gastroenterology (Gastroenterology) Vol. 136 Issue 2 Pg. 575-84.e2 (Feb 2009) ISSN: 1528-0012 [Electronic] United States
• PMID: 19111727 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Caveolin 1
• Dextran Sulfate

Topics

• Animals
• Caveolae (pathology)
• Caveolin 1 (genetics, metabolism)
• Cell Adhesion (physiology)
• Colitis (chemically induced, metabolism, physiopathology)
• Dextran Sulfate
• Disease Models, Animal
• Endothelium, Vascular (metabolism, pathology)
• Leukocytes (pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neovascularization, Pathologic (metabolism, pathology, physiopathology)