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We evaluated effects of endothelium removal and of endothelium-derived vasoactive agents on DNA synthesis and contractility in the isolated arterial wall. The experiments were performed on renal artery segments that had been 1) isolated from adult rats, 2) suspended in tissue culture for 3 days in the continuous presence of fetal calf serum, and 3) exposed for the last 24 h to 5-bromo-2'-deoxyuridine. Nuclear incorporation of this thymidine analogue was visualized by immunohistochemistry and used as an index of DNA synthesis. Tissue culture did not alter relaxing responses to guanosine 3',5'-cyclic monophosphate (cGMP)-generating agents but promoted relaxing responses to adenosine 3',5'-cyclic monophosphate (cAMP)-generating agents. It stimulated DNA synthesis in the endothelium, media, and adventitia. Mechanical removal of endothelium increased intra-arterial DNA synthesis. This was most prominent in the media. In preparations with endothelium, indomethacin and methylene blue did not enhance DNA synthesis. In segments that had been denuded of endothelium, atrial natriuretic factor, forskolin, iloprost, and prostaglandin E2, but not isobutylmethylxanthine or sodium nitroprusside, significantly reduced intra-arterial DNA synthesis. These data indicate that endothelium removal promotes the mitogenic response of the arterial wall to exogenous growth factors. This cannot be attributed to inhibitory influences of endothelium-derived relaxing factor or prostaglandins released by the endothelium under basal conditions.