Published online before print October 4, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.060968

Accepted for publication August 3, 2007.

Article

Caveolin-1 Is Critical for the Maturation of Tumor Blood Vessels through the Regulation of Both Endothelial Tube Formation and Mural Cell Recruitment

Julie DeWever^*, Françoise Frérart^*, Caroline Bouzin^*, Christine Baudelet, Réginald Ansiaux, Pierre Sonveaux^*, Bernard Gallez, Chantal Dessy^*, and Olivier Feron^*@

From the Unit of Pharmacology and Therapeutics (UCL-FATH 5349),* and the Biomedical Magnetic Resonance Unit, Université catholique de Louvain, Brussels, Belgium

^@ To whom correspondence should be addressed. E-mail: olivier.feron{at}uclouvain.be.

	Abstract

In the normal microvasculature, caveolin-1, the structural protein of caveolae, modulates transcytosis and paracellular permeability. Here, we used caveolin-1-deficient mice (Cav^-/-) to track the potential active roles of caveolin-1 down-modulation in the regulation of vascular permeability and morphogenesis in tumors. In B16 melanoma-bearing Cav^-/- mice, we found that fibrinogen accumulated in early-stage tumors to a larger extent than in wild-type animals. These results were confirmed by the observations of a net elevation of the interstitial fluid pressure and a relative deficit in albumin extravasation in Cav^-/- tumors (versus healthy tissues). Immunostaining analyses of Cav^-/- tumor sections further revealed a higher density of CD31-positive vascular structures and a dramatic deficit in -smooth muscle actin-stained mural cells. The increase in blood plasma volume in Cav^-/- tumors was confirmed by dynamic contrast enhanced-magnetic resonance imaging and found to be associated with a more rapid tumor growth. Finally, an in vitro wound test and the aorta ring assay revealed that silencing caveolin expression could directly impair the migration and the outgrowth of smooth muscle cells/pericytes, particularly in response to platelet-derived growth factor. In conclusion, a decrease in caveolin abundance, by promoting angiogenesis and preventing its termination by mural cell recruitment, appears as an important control point for the formation of new tumor blood vessels. Caveolin-1 therefore has the potential to be a marker of tumor vasculature maturity that may help adjusting anticancer therapies.

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