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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1831.)
© 2005 American Heart Association, Inc.

Vascular Biology

Signal-Crosstalk Between Rho/ROCK and c-Jun NH₂-Terminal Kinase Mediates Migration of Vascular Smooth Muscle Cells Stimulated by Angiotensin II

Haruhiko Ohtsu; Mizuo Mifune; Gerald D. Frank; Shuichi Saito; Tadashi Inagami; Shokei Kim-Mitsuyama; Yoh Takuwa; Terukatsu Sasaki; Jeffrey D. Rothstein; Hiroyuki Suzuki; Hidekatsu Nakashima; Elethia A. Woolfolk; Evangeline D. Motley; Satoru Eguchi

From the Cardiovascular Research Center (H.O., M.M., H.S., H.N., S.E.), Temple University School of Medicine, Philadelphia, Penn; the Department of Biochemistry (G.D.F., S.S., T.I.), Vanderbilt University School of Medicine, Nashville, Tenn; the Department of Pharmacology and Molecular Therapeutics (S.K.-M.), Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; the Department of Physiology (Y.T.), Kanazawa University School of Medicine, Ishikawa, Japan; the Department of Biochemistry (T.S.), Sapporo Medical University, Sapporo, Japan; the Department of Neurology and Neuroscience (J.D.R.), Johns Hopkins University, Baltimore, Md; and the Department of Anatomy and Physiology (E.A.W., E.D.M.), Meharry Medical College, Nashville, Tenn.

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

Background— Rho and its effector Rho-kinase/ROCK mediate cytoskeletal reorganization as well as smooth muscle contraction. Recent studies indicate that Rho and ROCK are critically involved in vascular remodeling. Here, we tested the hypothesis that Rho/ROCK are critically involved in angiotensin II (Ang II)-induced migration of vascular smooth muscle cells (VSMCs) by mediating a specific signal cross-talk.

Methods and Results— Immunoblotting demonstrated that Ang II stimulated phosphorylation of a ROCK substrate, regulatory myosin phosphatase targeting subunit (MYPT)-1. Phosphorylation of MYPT-1 as well as migration of VSMCs induced by Ang II was inhibited by dominant-negative Rho (dnRho) or ROCK inhibitor, Y27632. Ang II–induced c-Jun NH₂-terminal kinase (JNK) activation, but extracellular signal-regulated kinase (ERK) activation was not mediated through Rho/ROCK. Thus, infection of adenovirus encoding dnJNK inhibited VSMC migration by Ang II. We have further demonstrated that the Rho/ROCK activation by Ang II requires protein kinase C- (PKC) and proline-rich tyrosine kinase 2 (PYK2) activation, but not epidermal growth factor receptor transactivation. Also, VSMCs express PDZ-Rho guanine nucleotide exchange factor (GEF) and Ang II stimulated PYK2 association with tyrosine phosphorylated PDZ-RhoGEF.

Conclusions— PKC/PYK2-dependent Rho/ROCK activation through PDZ-RhoGEF mediates Ang II–induced VSMC migration via JNK activation in VSMCs, providing a novel mechanistic role of the Rho/ROCK cascade that is involved in vascular remodeling.

By using vascular smooth muscle cells (VSMCs) in culture, we have investigated signal cross-talk in mediating VSMC migration induced by angiotensin II. We found that Rho-kinase/ROCK activated by PYK2 and PKC-delta specifically mediate angiotensin II–induced VSMC migration via JNK activation, providing a potential cascade in mediating vascular remodeling.

Key Words: angiotensin II • Rho kinase/ROCK • c-jun NH₂-terminal kinase • vascular smooth muscle cells • migration

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