Circulation Research. 2001
Published online before print October 18, 2001, doi: 10.1161/hh2201.100319
Published online before print October 18, 2001, doi: 10.1161/hh2201.100319
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Submitted on July 3, 2001
Revised on October 5, 2001
Accepted on October 5, 2001
Hsp90 and Caveolin Are Key Targets for the Proangiogenic Nitric Oxide--Mediated Effects of Statins
From the Department of Medicine, University of Louvain Medical School, Brussels, Belgium.
* To whom correspondence should be addressed. E-mail: feron{at}mint.ucl.ac.be.
3-Hydroxy-3-methylglutaryl (HMG)--coenzyme A reductase inhibitors or statins exert direct beneficial effects on the endothelium in part through an increase in nitric oxide (NO) production. Here, we examined whether posttranslational modifications of the endothelial NO synthase (eNOS) could account for the proangiogenic effects of statins. We used endothelial cells (ECs) isolated from cardiac microvasculature, aorta, and umbilical veins, as well as dissected microvessels and aortic rings, that were cultured on reconstituted basement membrane matrix (Matrigel). Tube or precapillary formation was evaluated after statin treatment, in parallel with immunoblotting and immunoprecipitation experiments. Atorvastatin stimulated NO-dependent angiogenesis from both isolated and outgrowing (vessel-derived) ECs, independently of changes in eNOS expression. We found that in macro- but not microvascular ECs, atorvastatin stabilized tube formation through a decrease in caveolin abundance and its inhibitory interaction with eNOS. We also identified the chaperone protein hsp90 as a key target for the proangiogenic effects of statins. Using geldanamycin, an inhibitor of hsp90 function, and overexpression of recombinant hsp90, we documented that the statin-induced phosphorylation of eNOS on Ser1177 was directly dependent on the ability of hsp90 to recruit Akt in the eNOS complex. Finally, we showed that statin promoted the tyrosine phosphorylation of hsp90 and the direct interaction of hsp90 with Akt, which further potentiated the NO-dependent angiogenic processes. Our study provides new mechanistic insights into the NO-mediated angiogenic effects of statins and underscores the potential of these drugs and other modulators of hsp90 and caveolin abundance to promote neovascularization in disease states associated or not with atherosclerosis.
Key words: statin • angiogenesis • nitric oxide • hsp90 • caveolin
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