Erythropoietin accelerates smooth muscle cell-rich vascular lesion formation in mouse through endothelial cell activation involving enhanced PDGF-BB release

In this study, the effect of human erythropoietin delta (Epo) on SMC-rich lesions was evaluated. Mice, of which the left carotid artery was ligated, were treated with sub-erythropoietic as well as erythropoietic doses of Epo. Treatment with both doses of Epo enhanced SMC-rich lesion formation in ligated carotid arteries, and no association was observed between hemoglobin levels and neointima size. Moreover, endothelial progenitor cell (EPC) numbers in the peripheral blood increased in the erythropoietic but not in the sub-erythropoietic dosing group, indicating that EPC numbers did not correlate with lesion size. Immunohistochemical analysis of ligated arteries revealed that Epo-mediated enhancement of lesion formation correlates with increased Stat5 phosphorylation in the vessel wall. Experiments performed in cultured vascular cells demonstrated that Epo robustly induced phosphorylation of Stat5 in HUVECs, but only very weakly in human SMCs. In TNF-alpha activated endothelial cells Epo induced expression of PDGF-B, which was at least partially responsible for the induction of Stat5 phosphorylation in SMCs by endothelial cell conditioned medium. In conclusion, both sub-erythropoietic and erythropoietic doses of Epo accelerate SMC-rich neointima formation in mouse, which correlate with increased Stat5 phosphorylation in the vessel wall, but was independent of erythrocyte and EPC numbers