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PNAS 102 (1): 204-209

Copyright © 2005 by the National Academy of Sciences.


MEDICAL SCIENCES

Endothelial-specific expression of caveolin-1 impairs microvascular permeability and angiogenesis

Philip M. Bauer *, Jun Yu *, Yan Chen *, Reed Hickey {dagger}, Pascal N. Bernatchez *, Robin Looft-Wilson *, Yan Huang {dagger}, Frank Giordano {dagger}, Radu V. Stan {ddagger}, and William C. Sessa *, §

*Departments of Pharmacology and Vascular Cell Signaling and Therapeutics Program, Boyer Center for Molecular Medicine, and {dagger}Medicine and Cardiovasculate Gene Therapy Program, Yale University School of Medicine, New Haven, CT 06536; and {ddagger}Department of Pathology, Dartmouth Medical School, Lebanon, NH 03756

Edited by Louis J. Ignarro, University of California School of Medicine, Los Angeles, CA

Accepted for publication November 22, 2004.

Received for publication August 18, 2004.

Abstract: The functions of caveolae and/or caveolins in intact animals are beginning to be explored. Here, by using endothelial cell-specific transgenesis of the caveolin-1 (Cav-1) gene in mice, we show the critical role of Cav-1 in several postnatal vascular paradigms. First, increasing levels of Cav-1 do not increase caveolae number in the endothelium in vivo. Second, despite a lack of quantitative changes in organelle number, endothelial-specific expression of Cav-1 impairs endothelial nitric oxide synthase activation, endothelial barrier function, and angiogenic responses to exogenous VEGF and tissue ischemia. In addition, VEGF-mediated phosphorylation of Akt and its substrate, endothelial nitric oxide synthase, were significantly reduced in VEGF-treated Cav-1 transgenic mice, compared with WT littermates. The inhibitory effect of Cav-1 expression on the Akt-endothelial nitric oxide synthase pathway was specific because VEGF-stimulated phosphorylation of mitogen-activated protein kinase (ERK1/2) was elevated in the Cav-1 transgenics, compared with littermates. These data strongly support the idea that, in vivo, Cav-1 may modulate signaling pathways independent of its essential role in caveolae biogenesis.

Key Words: nitric oxide • caveolae • VEGF • signal transduction


Author contributions: R.H., F.G., and W.C.S. designed research; P.M.B., J.Y., Y.C., P.N.B., R.L.-W., Y.H., and R.V.S. performed research; P.M.B., R.V.S., and W.C.S. analyzed data; and W.C.S. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: TG, transgenic; Cav, caveolin; NO, nitric oxide; eNOS, endothelial NO synthase; PE, phenylephrine; ACh, acetylcholine; L-NAME, L-nitro arginine methyl ester; RT, room temperature; PECAM, platelet-endothelial cell adhesion molecule.

§ To whom correspondence should be addressed. E-mail: william.sessa{at}yale.edu.

© 2005 by The National Academy of Sciences of the USA


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