MITOGENIC EFFECT OF ERYTHROPOIETIN ON VAS CULAR SMOOTH-MUSCLE CELLS FROM SPONTANEOUSLY HYPERTENSIVE AND NORMOTENSIVE RATS

The administration of recombinant erythropoietin (rHuEPo) to anemic ch ronic renal failure patients may be associated with an increase in blo od pressure, possibly by direct effects on peripheral blood vessels. I n the present study, experiments were designed to explore the hypothes is that rHuEpo could enhance vascular resistance through mitogenic eff ect on vascular smooth muscle cells (VSMCs), and that preexisting hype rtension might be a predisposing condition. Cultured VSMCs from the th oracic aortae of spontaneously hypertensive (SHR) and normotensive Wis tar-Kyoto (WKY) rats were studied for DNA synthesis, phospholipase C a ctivity, and cell growth related proto-oncogene expression in the pres ence of rHuEpo. In cells from both strains, rHuEpo dose-dependently in creased DNA synthesis and stimulated phospholipase C activity, as indi cated by H-3-thymidine incorporation and H-3-inositol phosphate format ion, respectively (EC50 almost-equal-to 4 U/ml). Exposure of VSMCs to rHuEpo for various times gradually increased the levels of c-myc and j unB and transiently induced c-fos expression, as determined by Norther n analysis. rHuEpo-induced DNA synthesis was markedly enhanced in VSMC s from SHR compared to those from WKY. In contrast, rHuEpo-induced pho spholipase C activity and proto-oncogene expression did not differ bet ween the two strains. Taken together, these results suggest that rHuEp o may function as a vascular smooth muscle cell growth promoting facto r through activation of the phospholipase C cascade and modulation of proto-oncogene expression. It could thereby contribute to vascular hyp ertrophy and arterial hypertension.