Angiotensin II‐induced migration of vascular smooth muscle cells (VSMCs) is mediated by both 72‐KDa spleen tyrosine kinase (Syk) via p38‐MAPK activated c‐Src and by ERK1/2 via c‐Src‐induced EGFR transactivation

Abstract

We have previously shown that angiotensin II (Ang II)‐induced VSMC hypertrophy is mediated by activation of Syk via p38‐MAPK stimulated phosphorylation of c‐Src. However, Ang II‐induced proliferation of VSMCs is mediated through transactivation of EGFR. The purpose of this study was to examine the contribution of Syk and EGFR in Ang II‐induced migration of aortic VSMCs using the wound healing technique. Ang II (200nM) treatment for 24 hours increased VSMC migration by 100% (p < 0.05). Ang II‐inducedmigration of VSMC and Syk phosphorylation, as determined by WB analysis, was inhibited by piceatannol (10μM), a tyrosine kinase inhibitor, and by transfection of VSMCs with dominantnegative (DN) but not wild type (WT) Syk plasmids. Ang II‐induced VSMC migration and Syk phosphorylation was attenuated by inhibitors of p38‐MAPK (SB202190) (20μM) and c‐Src (PP2) (10μM) and by DN c‐Src but not partially active c‐Src. Ang II‐induced VSMC migration and EGFR phosphorylation was also inhibited by EGFR blocker AG1478 (2μM). ERK1/2 inhibitor U0126 (10μM) attenuated Ang II‐induced cell migration, and ERK1/2 but not EGFR phosphorylation. c‐Src inhibitor PP2, reduced EGFR and ERK1/2 phosphorylation. These data suggest that Ang II stimulates VSMC migration via Syk through p38‐MAPK activated c‐Src, and via ERK1/2 through c‐Src induced EGFR transactivation (Supported by NIH Grant 079109 from HLBI).