Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 1, Pages 204-209Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0406092102
Keywords
nitric oxide; caveolae; VEGF; signal transduction
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Funding
- NHLBI NIH HHS [R01 HL 64793, N01 HV 28186, R01 HL057665, P01 HL070295, R01 HL 61371, R01 HL061371, R01 HL065418-02, R01 HL064793, F32 HL 07216-01, R01 HL065418, R01 HL065418-03, R01 HL065418-01A1, F32 HL072618, P01 HL 70295, R01 HL 57665, R01 HL065418-04, N01HV28186] Funding Source: Medline
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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.
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