Therapeutic angiogenesis: new indication for endothelial NO synthase gene transfer.

Evidence continues to accumulate on the importance of NO in angiogenesis.1–7 A number of angiogenic substances, including vascular endothelial growth factor (VEGF), stimulate production of NO in endothelial cells.8,9 In vivo biosynthesis of NO is essential for angiogenesis induced by tissue ischemia.3 Angiogenesis is severely impaired in ischemic hindlimb of endothelial NO synthase (eNOS)deficient mice.3,10 This impairment is not corrected by administration of VEGF, strongly suggesting that NO is downstream signal for angiogenic effect of VEGF. Indeed, in vascular endothelial cells, VEGF increases eNOS enzymatic activity via activation of protein kinase Akt and subsequent phosphorylation of eNOS.11,12 More recent study demonstrated that 3-hydroxyl-3-methyl coenzyme A (HMG-CoA) reductase inhibitor simvastatin also promotes angiogenesis by activation of protein kinase Akt.13 This effect seems to be mediated by stimulation of eNOS enzymatic activity. The importance of protein kinase Akt in regulation of NO production in vivo was demonstrated by adenovirus-mediated delivery of active Akt into the vascular wall. Overexpression of Akt increased resting blood flow, whereas expression of dominant negative Akt inhibited endothelium-dependent relaxation mediated by NO.14 Thus, phosphorylation of eNOS by protein kinase Akt seems to be a major molecular mechanism underlying the angiogenic effect of VGEF and statins.