Mitogenic effect of erythropoietin on cultured aortic myocytes

The administration of recombinant erythropoietin (rHuEpo) to anemic chronic renal failure patients may be associated with an increase in blood pressure, possibly by direct effects on peripheral blood vessels. In the present study, experiments were designed to explore the hypothesis that rHuEpo could enhance vascular resistance through mitogenic effect on vascular smooth muscle cells (VSMCs), and that preexisting hypertension might be a predisposing condition. Cultured VSMCs from the thoracic aortae of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats were studied for DNA synthesis, phospholipase C activity, and cell growth related proto-oncogene expression in the presence of rHuEpo. In cells from both strains, rHuEpo dose-dependently increased DNA synthesis and stimulated phospholipase C activity, as indicated by 3H-thymidine incorporation and 3H-inositol phosphate formation, respectively (EC50 approximately 4 U/ml). Exposure of VSMCs to rHuEpo for various times gradually increased the levels of c-myc and junB and transiently induced c-fos expression, as determined by Northern analysis. rHuEpo-induced DNA synthesis was markedly enhanced in VSMCs from SHR compared to those from WKY. In contrast, rHuEpo-induced phospholipase C activity and proto-oncogene expression did not differ between the two strains. Taken together, these results suggest that rHuEpo may function as a vascular smooth muscle cell growth promoting factor through activation of the phospholipase C cascade and modulation of proto-oncogene expression. It could thereby contribute to vascular hypertrophy and arterial hypertension.