Endothelial caveolin-1 regulates pathologic angiogenesis in a mouse model of colitis.
OBJECTIVE
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.
Chidlow
John H
JH
Department of Pathology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana 71130, USA.
Greer
Joshua J M
JJ
Anthoni
Christoph
C
Bernatchez
Pascal
P
Fernandez-Hernando
Carlos
C
Fernadez-Hernando
Carlos
C
Bruce
Megan
M
Abdelbaqi
Maisoun
M
Shukla
Deepti
D
Granger
D Neil
DN
Sessa
William C
WC
Kevil
Christopher G
CG
D000818:Animals; D021941:Caveolae / Q000473:pathology; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
D051242:Caveolin 1; D016264:Dextran Sulfate