Distinct G proteins mediate the EGFR transactivation pathway and the Rho/Rho‐kinase (ROCK) pathway activated by angiotensin II in vascular smooth muscle cells.

Abstract

Angiotensin II (AngII) and its G protein-coupled AT1 receptor, play critical roles in mediating cardiovascular diseases, in part through the induction of hypertrophy and hyperplasia of vascular smooth muscle cells (VSMCs). The AT1 receptor appears to have two major growth-promoting pathways, the EGFR/ERK and Rho/ROCK pathways in VSMCs. This study examines the requirement of select G protein(s) on these pathways that lead to vascular remodeling. Intracellular Ca2+ elevation induced by AngII but not by PDGF was completely inhibited by a selective Gq inhibitor, YM-254890. In addition, EGFR and ERK activation induced by AngII, but not Ca2+ ionophore, was inhibited by YM. Also, YM partially inhibited AngII-induced phosphorylation of MYPT, a substrate of ROCK. Thus, AngII activates G12/13 as selectively measured with the GST-TPR pull-down assay. Stimulation of quiescent VSMCs with AngII for 72 h resulted in an increase of cellular protein and cell volume, but not in proliferation. YM completely inhibited these hypertrophic effects. However, a G protein-independent AT1 receptor agonist did not stimulate the EGFR or the Rho/ROCK pathway in VSMCs. Furthermore, adenovirus encoding a Gq inhibitor completely inhibited the EGFR/ERK pathway and partially inhibited the Rho/ROCK pathway activated by AngII. These results suggest that Gq plays a major role in the EGFR/ERK pathway leading to vascular hypertrophy induced by AngII, whereas both Gq and G12/13 partially participates in the Rho/ROCK pathway.