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

Angiotensin II (AngII) and its G protein‐coupled AT 1 receptor, play critical roles in mediating cardiovascular diseases, in part through the induction of hypertrophy and hyperplasia of vascular smooth muscle cells (VSMCs). The AT 1 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 Ca 2+ elevation induced by AngII but not by PDGF was completely inhibited by a selective G q inhibitor, YM‐254890. In addition, EGFR and ERK activation induced by AngII, but not Ca 2+ ionophore, was inhibited by YM. Also, YM partially inhibited AngII‐induced phosphorylation of MYPT, a substrate of ROCK. Thus, AngII activates G 12/13 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 AT 1 receptor agonist did not stimulate the EGFR or the Rho/ROCK pathway in VSMCs. Furthermore, adenovirus encoding a G q inhibitor completely inhibited the EGFR/ERK pathway and partially inhibited the Rho/ROCK pathway activated by AngII. These results suggest that G q plays a major role in the EGFR/ERK pathway leading to vascular hypertrophy induced by AngII, whereas both G q and G 12/13 partially participates in the Rho/ROCK pathway.