Angiotensin II promotes smooth muscle cell proliferation and migration through release of heparinbinding epidermal growth factor and activation of EGF-receptor pathway. Mol Cells 2005;20:263–270

Transactivation of EGF-receptor (EGFR) by G-protein coupled receptors (GPCRs) is emerging as an important pathway in cell proliferation, which plays a crucial role in the development of atherosclerotic lesion. An-giotensin II (Ang II) has been identified to have a ma-jor role in the formation of atherosclerotic lesions, al-though the underlying mechanisms remain largely unclear. We hypothesize that Ang II promotes the pro-liferation and migration of smooth muscle cells through the release of heparin-binding epidermal growth factor like growth factor (HB-EGF), transacti-vation of EGFR and activation of Akt and Erk 1/2, with matrix metalloproteases (MMPs) playing a dis-pensable role. Primary rat aortic smooth muscle cells were used in this study. Smooth muscle cells rendered quiescent by serum deprivation for 12 h were treated with Ang II (100 nM) in the presence of either GM6001 (20 µM), a specific inhibitor of MMPs or AG1478 (10 µM), an inhibitor of EGFR. The levels of phosphorylation of EGFR, Akt and Erk 1/2 were as-sessed in the cell lysates. Inhibition of MMPs by GM6001 significantly attenuated Ang II-stimulated phosphorylation of EGFR, suggesting that MMPs may be involved in the transactivation of EGFR by Ang II receptor. Furthermore Ang II-stimulated proliferation and migration of smooth muscle cells were signifi-cantly blunted by inhibiting MMPs and EGFR and applying HB-EGF neutralization antibody, indicating that MMPs, HB-EGF and EGFR activation is neces-sary for Ang-II stimulated migration and proliferation of smooth muscle cells. Our results suggest that inhibi