Erythropoietin improves cardiac function through endothelial progenitor cell and vascular endothelial growth factor mediated neovascularization

TLDR

Erythropoietin (EPO) improves cardiac function and induces neovascularization in chronic heart failure, but its precise mechanism remains unclear. The study aimed to determine how EPO affects the homing and incorporation of endothelial progenitor cells (EPC) into the myocardial microvasculature and the expression of angiogenic factors. Using a rat myocardial infarction model with hPAP‑transgenic bone marrow, the authors administered darbepoetin alfa (40 µg/kg every 3 weeks starting 3 weeks post‑MI) and evaluated longitudinal left‑ventricular function, circulating EPC, myocardial histology, and VEGF expression 9 weeks after MI. EPO treatment prevented LV dilation, improved cardiac function, and increased capillary density by 42 %, driven by a three‑fold rise in EPC homing and a 4.5‑fold upregulation of myocardial VEGF that together promoted neovascularization.

Abstract

Erythropoietin (EPO) improves cardiac function and induces neovascularization in chronic heart failure (CHF), although the exact mechanism has not been elucidated. We studied the effects of EPO on homing and incorporation of endothelial progenitor cells (EPC) into the myocardial microvasculature and myocardial expression of angiogenic factors. CHF was induced in rats by coronary artery ligation resulting in myocardial infarction (MI) after bone marrow had been replaced by human placental alkaline phosphatase (hPAP) transgenic cells. We studied the effects of darbepoetin alfa treatment (EPO, 40 µg/kg, every 3 weeks, starting 3 weeks after MI) on longitudinal changes in left ventricular (LV) function, circulating EPC, myocardial histology, and expression of vascular endothelial growth factor (VEGF) determined 9 weeks after MI. EPO prevented LV-dilatation and improved cardiac function (all P < 0.05), which was associated with 42% increased capillary growth (P < 0.01). EPO-induced mobilization of EPC from the bone marrow (P < 0.01), which resulted in a three-fold increased homing of EPC into the cardiac microvasculature. The percentage of the endothelium that consisted of bone marrow derived cells was significantly increased (3.9 ± 0.5 vs. 11.4 ± 1%, P < 0.001) comprising 30% of the newly formed capillaries. In addition, EPO treatment resulted in a 4.5-fold increased myocardial expression of VEGF, which correlated strongly with neovascularization (r = 0.67; P < 0.001). VEGF was equally expressed by endothelial cells of myocardial and bone marrow origin. EPO-induced neovascularization in post-MI heart failure is mediated through a combination of EPC recruitment from the bone marrow and increased myocardial expression of VEGF.