Endothelial Nitric Oxide Synthase Inhibits G12/13 and Rho-Kinase Activated by the Angiotensin II Type-1 Receptor

Background— Although, endothelial nitric oxide (NO) synthase (eNOS) is believed to antagonize vascular remodeling induced by the angiotensin II (AngII) type-1 receptor, the exact signaling mechanism remains unclear. Methods and Results— By expressing eNOS to vascular smooth muscle cells (VSMCs) via adenovirus, we investigated a signal transduction mechanism of the eNOS gene transfer in preventing vascular remodeling induced by AngII. We found marked inhibition of AngII-induced Rho/Rho-kinase activation and subsequent VSMC migration by eNOS gene transfer whereas Gq-dependent transactivation of the epidermal growth factor receptor by AngII remains intact. This could be explained by the specific inhibition of G12/13 activation by eNOS-mediated G12/13 phosphorylation. Conclusion— The eNOS/NO cascade specifically targets the Rho/Rho-kinase system via inhibition of G12/13 to prevent vascular migration induced by AngII, representing a novel signal cross-talk in cardiovascular protection by NO.