NITRIC-OXIDE MEDIATES MITOGENIC EFFECT OF VEGF ON CORONARY VENULAR ENDOTHELIUM

Vascular endothelial growth factor (VEGF) is a secreted protein that i s a specific growth factor for endothelial cells. We have recently dem onstrated that nitric oxide (NO) donors and vasoactive peptides promot ing NO-mediated vasorelaxation induce angiogenesis in vivo as well as endothelial cell growth and motility in vitro; in contrast, inhibitors of NO synthase suppress angiogenesis. In this study we investigated t he role of NO in mediating the mitogenic effect of VEGF on cultured mi crovascular endothelium isolated from coronary postcapillary venules. VEGF induced a dose-dependent increase in cell proliferation and DNA s ynthesis. The role of NO was determined by monitoring proliferation or guanosine 3',5'-cyclic monophosphate (cGMP) levels in the presence an d absence of NO synthase blockers. The proliferative effect evoked by VEGF was reduced by pretreatment of the cells with NO synthase inhibit ors. Exposure of the cells to VEGF induced a significant increment in cGMP levels. This effect was potentiated by superoxide dismutase addit ion and was abolished by NO synthase inhibitors. VEGF stimulates proli feration of postcapillary endothelial cells through the production of NO and cGMP accumulation.