Altered angiogenesis in caveolin-1 gene-deficient mice is restored by ablation of endothelial nitric oxide synthase

Morais, Christudas, Ebrahem, Quteba, Anand-Apte, Bela and Parat, Marie-Odile (2012) Altered angiogenesis in caveolin-1 gene-deficient mice is restored by ablation of endothelial nitric oxide synthase. American Journal of Pathology, 180 4: 1702-1714.

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Author Morais, Christudas
Ebrahem, Quteba
Anand-Apte, Bela
Parat, Marie-Odile
Title Altered angiogenesis in caveolin-1 gene-deficient mice is restored by ablation of endothelial nitric oxide synthase
Journal name American Journal of Pathology  (ERA 2012 Listed)    (ERA 2010 Rank A*)   Check publisher's open access policy
Publication date 2012-04
Sub-type Article
DOI 10.1016/j.ajpath.2011.12.018
Volume number 180
Issue number 4
ISSN 0002-9440; 1525-2191
Start page 1702
End page 1714
Total pages 13
Place of publication New York, NY, United States
Publisher Elsevier
Collection year 2013
Language eng
Abstract Caveolin-1 is an essential structural protein of caveolae, specialized plasma membrane organelles highly abundant in endothelial cells, where they regulate multiple functions including angiogenesis. Caveolin-1 exerts a tonic inhibition of endothelial nitric oxide synthase (eNOS) activity. Accordingly, caveolin-1 genedisrupted mice have enhanced eNOS activity as well as increased systemic nitric oxide (NO) levels. We hypothesized that excess eNOS activity, secondary to caveolin deficiency, would mediate the decreased angiogenesis observed in caveolin-1 genedisrupted mice. We tested tumor angiogenesis in mice lacking either one or both proteins, using in vitro, ex vivo, and in vivo assays. We show that endothelial cell migration, tube formation, cell sprouting from aortic rings, tumor growth, and angiogenesis are all significantly impaired in both caveolin-1null and eNOS-null mice. We further show that these parameters were either partially or fully restored in double knockout mice that lack both caveolin-1 and eNOS. Furthermore, the effects of genetic ablation of eNOS are mimicked by the administration of the NOS inhibitor N-nitro-l-arginine methyl ester hydrochloride (L-NAME), including the reversal of the caveolin-1null mouse angiogenic phenotype. This study is the first to demonstrate the detrimental effects of unregulated eNOS activity on angiogenesis, and shows that impaired tumor angiogenesis in caveolin-1null mice is, at least in part, the result of enhanced eNOS activity.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online 6 February 2012.

 
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Created: Mon, 23 Apr 2012, 15:06:50 EST by Myrtle Sahabandu on behalf of School of Pharmacy