EFFECT OF ERYTHROPOIETIN ON DNA-SYNTHESIS, PROTOONCOGENE EXPRESSION AND PHOSPHOLIPASE-C ACTIVITY IN RAT VASCULAR SMOOTH-MUSCLE CELLS

The administration of recombinant human erythropoietin (rHuEpo) to ane mic chronic renal. failure patients may be associated with an increase in blood pressure, possibly by direct effects on peripheral blood ves sels. The experiments of the present study were designed to explore th e hypothesis that rHuEpo might exert mitogenic effects on vascular smo oth muscle cells (VSMCs), and that pre-existing hypertension might be a predisposing condition. Cultured aortic VSMCs from spontaneously hyp ertensive (SHR) and normotensive Wistat-Kyoto (WKY) rats were studied for DNA synthesis, phospholipase C activity, and cell growth related p roto-oncogene expression in the presence of rHuEpo. In cells from both rat strains, rHuEpo dose-dependently increased DNA synthesis and stim ulated phospholipase C activity, as indicated by H-3-thymidine incorpo ration and inositol phosphate formation, respectively. Exposure of VSM Cs to rHuEpo for various periods gradually increased the levels of c-m yc and JunB mRNAs and transiently induced c-fos mRNA expression as det ermined by Northern analysis. The hormone-induced DNA synthesis was ma rkedly enhanced in VSMCs from SHR compared to those from WKY. In contr ast, rHuEpo-induced phospholipase C activity and proto-oncogene expres sion did not differ between the two strains. Taken togeteher, these re sults suggest that rHuEpo may function as a vascular smooth muscle cel l growth promoting factor through activation of the phospholipase C ca scade and a modulation of proto-oncogene expression. It could thereby contribute to vascular hypertrophy and arterial hypertension. (C) 1994 Academic Press, Inc.