Endothelin-1 stimulates DNA synthesis of vascular smooth-muscle cells through transactivation of epidermal growth factor receptor

To elucidate the molecular mechanism of the mitogenic effect of endothelin-1 (ET-1) on vascular smooth-muscle cells (VSMCs), we studied the effect of AG1478, a novel epidermal growth factor receptor (EGFR) kinase inhibitor, on p42/44 mitogen-activated protein (MAP) kinase activation, c-Fos expression, and DNA synthesis stimulated by ET-1. AG1478 dose-dependently (2.5 x 10(-8) M-2.5 x 10(-7) M) inhibited ET-1-induced MAP kinase activation. The ET-1-induced c-Fos protein expression was inhibited by AG1478 (2.5 x 10(-7) M). AG1478 also dose-dependently inhibited ET-1-stimulated [3H]thymidine incorporation. These data suggest that ET-1 induces MAP kinase activation, c-Fos expression, and promotes proliferation of VSMCs via transactivation of EGFR.