Hsp90 and caveolin are key targets for the proangiogenic nitric oxide-mediated effects of statins

3-Hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase inhibitors or statins exert direct beneficial effects on the endothelium in part through an incr ease in nitric oxide (NO) production. Here, we examined whether posttransla tional modifications of the endothelial NO synthase (eNOS) could account fo r the proangiogenic effects of statins. We used endothelial cells (ECs) iso lated from cardiac microvasculature, aorta, and umbilical veins, as well as dissected microvessels and aortic rings, that were cultured on reconstitut ed basement membrane matrix (Matrigel). Tube or precapillary formation was evaluated after statin treatment, in parallel with immunoblotting and immun oprecipitation experiments. Atorvastatin stimulated NO-dependent angiogenes is 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 st atins. Using geldanamycin, an inhibitor of hsp90 function, and overexpressi on of recombinant hsp90, we documented that the statin-induced phosphorylat ion of eNOS on Ser1177 was directly dependent on the ability of hsp90 to re cruit 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 s tudy provides new mechanistic insights into the NO-mediated angiogenic effe cts of statins and underscores the potential of these drugs and other modul ators of hsp90 and caveolin abundance to promote neovascularization in dise ase states associated or not with atherosclerosis.