Endothelial-specific expression of caveolin-1 impairs microvascular permeability and angiogenesis.
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.
Bauer
Philip M
PM
Department of Pharmacology and Vascular Cell Signaling and Therapeutics Program, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.
Yu
Jun
J
Chen
Yan
Y
Hickey
Reed
R
Bernatchez
Pascal N
PN
Looft-Wilson
Robin
R
Huang
Yan
Y
Giordano
Frank
F
Stan
Radu V
RV
Sessa
William C
WC
D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D051242:Caveolin 1; D022461:Caveolins / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D004727:Endothelium / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D040301:Vascular Endothelial Growth Factor Receptor-2