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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:217.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Endothelial Nitric Oxide Synthase Inhibits G_12/13 and Rho-Kinase Activated by the Angiotensin II Type-1 Receptor

Implication in Vascular Migration

Hiroyuki Suzuki; Keita Kimura; Heigoro Shirai; Kunie Eguchi; Sadaharu Higuchi; Akinari Hinoki; Kazuhiro Ishimaru; Eugen Brailoiu; Danny N. Dhanasekaran; Laura N. Stemmle; Timothy A. Fields; Gerald D. Frank; Michael V. Autieri; Satoru Eguchi

From the Cardiovascular Research Center, Department of Physiology (H. Suzuki, K.K., H. Shirai, K.E., S.H., A.H., K.I., M.V.A., S.E.), the Department of Pharmacology (E.B.), and Fels Institute for Cancer Research and Molecular Biology (D.N.D.), Temple University School of Medicine, Philadelphia, Pa; the Department of Pathology (L.N.S., T.A.F.), Duke University Medical Center, Durham, NC; and the Department of Biochemistry (G.D.F.), Vanderbilt University School of Medicine, Nashville, Tenn. Current affiliation for T.A.F.: Department of Pathology, The University of Kansas Medical Center.

Correspondence to Satoru Eguchi, MD, PhD, FAHA, Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, 3420 N Broad Street, Philadelphia, PA 19140. E-mail seguchi{at}temple.edu

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 G_q-dependent transactivation of the epidermal growth factor receptor by AngII remains intact. This could be explained by the specific inhibition of G_12/13 activation by eNOS-mediated G_12/13 phosphorylation.

Conclusion— The eNOS/NO cascade specifically targets the Rho/Rho-kinase system via inhibition of G_12/13 to prevent vascular migration induced by AngII, representing a novel signal cross-talk in cardiovascular protection by NO.

The effect of endothelial nitric oxide synthase (eNOS) gene transfer on signal cross-talk with Rho and Rho-kinase activated by angiotensin II was investigated. We found that eNOS inhibited the Rho/ROCK pathway activated by angiotensin II via inhibition of G_12/13. Because this leads to inhibition of vascular cell migration induced by angiotensin II, our findings reveal a novel signal cross-talk explaining vascular protection via nitric oxide.

Key Words: angiotensin II • vascular smooth muscle • G protein • nitric oxide synthase

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