To determine whether angiotensin II (Ang II) may modulate the control by endothelial cells of DNA synthesis in mesangial cells, we cocultured human umbilical vein endothelial cells (HUVEC) and human mesangial cells. HUVEC released endothelin-1 (ET-1), and prostaglandin I(2) (PGI(2)). Ang II stimulated the production of PGI(2), but did not modify that of ET-1. DNA synthesis in mesangial cells estimated by [3H]-thymidine incorporation was increased when mesangial cells and endothelial cells were cocultured. The mitogenic effect of endothelial cells in coculture resulted from ET-1 production since it was suppressed by bosentan, a mixed specific ET-1 receptor antagonist. The effects of Ang II on mesangial cell proliferation varied according to the protocol. Under control conditions, Ang II was inactive. In the presence of HUVEC-conditioned medium, Ang II exerted a mitogenic effect. By contrast, Ang II inhibited DNA synthesis by mesangial cells in the experiments of coculture. The latter effect could be attributed to HUVEC-released PGI(2) via the increase of cyclic AMP in mesangial cells since it was abolished by indomethacin, a cyclooxygenase inhibitor. In conclusion, endothelial cells may stimulate DNA synthesis in mesangial cells via ET-1 production and Ang II inhibits this effect by stimulating PGI(2) production in endothelial cells. In contrast, Ang II reinforces the mitogenic effect of the endothelial cell-conditioned medium when it acts directly on mesangial cells.