Erythropoietin-Mobilized Endothelial Progenitors Enhance Reendothelialization via Akt-Endothelial Nitric Oxide Synthase Activation and Prevent Neointimal Hyperplasia

TLDR

The study examined whether erythropoietin‑induced mobilization of endothelial progenitor cells enhances endothelial repair after arterial injury. Epo was administered to mice after femoral artery wire injury, stimulating mobilization and differentiation of bone‑marrow‑derived EPCs and proliferation of resident endothelial cells. Epo treatment reduced neointimal hyperplasia to 48% of control, increased reendothelialization by 1.4‑fold (55% from bone marrow), elevated circulating EPCs, promoted bone‑marrow‑derived endothelial cell incorporation, upregulated Epo receptor, activated Akt/eNOS‑mediated NO production, and exerted anti‑apoptotic effects, thereby preventing neointimal hyperplasia in a NO‑dependent manner.

Abstract

We investigated whether the mobilization of endothelial progenitor cells (EPCs) by exogenous erythropoietin (Epo) promotes the repair of injured endothelium. Recombinant human Epo was injected (1000 IU/kg for the initial 3 days) after wire injury of the femoral artery of mice. Neointimal formation was inhibited by Epo to 48% of the control (P<0.05) in an NO-dependent manner. Epo induced a 1.4-fold increase in reendothelialized area of day 14 denuded vessels, 55% of which was derived from bone marrow (BM) cells. Epo increased the circulating Sca-1(+)/Flk-1(+) EPCs (2.0-fold, P<0.05) with endothelial properties NO dependently. BM replacement by GFP- or beta-galactosidase-overexpressing cells showed that Epo stimulated both differentiation of BM-derived EPCs and proliferation of resident ECs. BM-derived ECs increased 2.2- to 2.7-fold (P<0.05) in the Epo-induced neoendothelium, where the expression of Epo receptor was upregulated. Epo induced Akt/eNOS phosphorylation and NO synthesis on EPCs and exerted an antiapoptotic action on wire-injured arteries. In conclusion, Epo treatment inhibits the neointimal hyperplasia after arterial injury in an NO-dependent manner by acting on the injured vessels and mobilizing EPCs to the neo-endothelium.