Endothelial nitric oxide synthase is essential for the HMG-CoA reductase inhibitor cerivastatin to promote collateral growth in response to ischemia

HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors, or st atins, are prescribed widely to lower cholesterol. Accumulating evidence in dicates that statins have various effects on vascular cells, which are inde pendent of their lipid-lowering effect. Here, we tested the hypothesis that statins may augment collateral flow to ischemic tissues. We induced hind-l imb ischemia in wild-type mice and treated them with either saline or ceriv astatin. Cerivastatin enhanced the blood flow recovery dramatically as dete rmined by Laser Doppler imaging. The mice treated with saline displayed fre quent autoamputation of the ischemic toe, which was prevented completely by cerivastatin. Anti-CD31 immunostaining revealed that cerivastatin signific antly increased the capillary density. Endothelial nitric oxide synthase (e NOS) activity was enhanced markedly in the mice treated with cerivastatin. The angiogenic effect of cerivastatin was abrogated in eNOS deficient (eNOS -/-) mice. These results indicate that eNOS is essential for cerivastatin t o promote collateral growth in response to ischemia.