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Central Role of G_q in the Hypertrophic Signal Transduction of Angiotensin II in Vascular Smooth Muscle Cells

Cardiovascular Research Center and Department of Physiology (H.O., S.H., H.Sh., K.E., H.Su., A.H., S.E.) and Department of Pharmacology (E.B.), Temple University School of Medicine, Philadelphia, Pennsylvania 19140; Center for Translational Medicine (A.D.E.), Thomas Jefferson University, Philadelphia, Pennsylvania 19107; and Department of Biochemistry (G.D.F.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Address all correspondence and requests for reprints to: Satoru Eguchi, M.D., Ph.D., F.A.H.A., Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, Pennsylvania 19140. E-mail: seguchi{at}temple.edu.

The angiotensin II (AngII) type 1 receptor (AT₁) plays a critical role in hypertrophy of vascular smooth muscle cells (VSMCs). Although it is well known that G_q is the major G protein activated by the AT₁ receptor, the requirement of G_q for AngII-induced VSMC hypertrophy remains unclear. By using cultured VSMCs, this study examined the requirement of G_q for the epidermal growth factor receptor (EGFR) pathway, the Rho-kinase (ROCK) pathway, and subsequent hypertrophy. AngII-induced intracellular Ca²⁺ elevation was completely inhibited by a pharmacological G_q inhibitor as well as by adenovirus encoding a G_q inhibitory minigene. AngII (100nM)-induced EGFR transactivation was almost completely inhibited by these inhibitors, whereas these inhibitors only partially inhibited AngII (100nM)-induced phosphorylation of a ROCK substrate, myosin phosphatase target subunit-1. Stimulation of VSMCs with AngII resulted in an increase of cellular protein and cell volume but not in cell number. The G_q inhibitors completely blocked these hypertrophic responses, whereas a G protein-independent AT₁ agonist did not stimulate these hypertrophic responses. In conclusion, G_q appears to play a major role in the EGFR pathway, leading to vascular hypertrophy induced by AngII. Vascular G_q seems to be a critical target of intervention against cardiovascular diseases associated with the enhanced renin-angiotensin system.

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