In human coronary smooth muscle cells (HCSMC), treatment with the vascular mitogen; endothelin-1 (ET-1), induced cell proliferation and stimulated ERK-1/2 phosphorylation at active sites. Pretreatment with the MEK-ERK inhibitor (PD98059) appreciably reversed the mitogenic effects of ET-1. On the other hand, pretreatment with the polyphenolic stilbene resveratrol (RSVL, 1-100 microM) triggered more prominent inhibition of ET-1-evoked cell proliferation and ERK1/2 activation. Besides, RSVL also markedly (2-3 fold) and rapidly enhanced cGMP formation, but had no effect on cAMP levels. This RSVL-evoked upregulation of cGMP was insensitive to pretreatment with the soluble guanylyl cyclase (sGC)-inhibitor (ODQ, 10 microM), but was ablated with an inhibitor of pGC (PMA, 0.1 microM). Further, pretreatment with the specific cGMP-phosphodiesterase inhibitor, zaprinast (10 microM) appreciably augmented RSVL-evoked cGMP formation, ERK inhibition, and cytostatic response. Moreover, the RSVL-induced ERK-inhibitory effects were significantly reversed by the kinase-G inhibitor, KT-5823 (10 microM; 69%), but not by the kinase-A inhibitor (KT-5720). These results demonstrate a novel signaling pathway for RSVL that leads from activation of the pGC/kinase-G system to inhibition of ERK1/2 and their downstream nuclear targets. This pathway functions to counteract the atherogenic signaling induced by vascular mitogens.