Defining the Mechanism of Erythropoietin's Vasoactive Properties in Resistance Arteries

Abstract

Clinically, erythropoietin (EPO) is known to increase systemic vascular resistance, however, in cell culture, EPO has been reported to increase activation of endothelial nitric oxide synthase (eNOS). How EPO can activate eNOS, while causing vasoconstriction, is likely due to EPO's ability to activate multiple receptors, the homodimeric EPO receptor (EPOR2) and the heterodimeric EPOR/beta common receptor (βCR). The purpose of this study was to investigate the contribution of each receptor in endothelial‐dependent vasodilation. We hypothesized that the vasoconstrictive effects seen with EPO administration are mediated through the EPOR2. To study the effects of each receptor, we utilized EPO and the EPO peptide (EPOp), which solely acts on the heterodimeric EPOR/βCR. Adult 16‐week old male C57BL/6 mice were euthanized and first order mesenteric arteries were isolated for in vitro study. Endothelium‐dependent (acetylcholine) and ‐independent (sodium nitroprusside) vasodilator responses were evaluated with and without an acute EPO (50 mIU/mL) or EPOp (25 ng/mL) pretreatment. We found that acetylcholine, endothelium‐dependent, vasodilation was impaired in arteries pretreated with both EPO and EPOp as compared to controls. However, while the EPOp vasodilation was impaired by 60%, EPO pretreatment totally inhibited acetylcholine‐induced vasodilation. Importantly EPO, EPOp and control treated arteries were all able to vasodilate equally in response to sodium nitroprusside, an endothelium‐independent vasodilator. These findings suggest that acute activation of the homodimeric EPOR2 or the heterodimeric EPOR/βCR can both lead to an endothelial specific impairment of vasodilator function in resistance arteries. We will discuss the putative mechanism of these effects along with the physiologic significance.