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(Circulation Research. 2006;98:1405.)
© 2006 American Heart Association, Inc.

Integrative Physiology

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

Norifumi Urao, Mitsuhiko Okigaki, Hiroyuki Yamada, Yasushi Aadachi, Kuniharu Matsuno, Akihiro Matsui, Shinsaku Matsunaga, Kento Tateishi, Tetsuya Nomura, Tomosaburo Takahashi, Tetsuya Tatsumi, Hiroaki Matsubara

From the Departments of Cardiovascular Medicine (N.U., M.O., H.Y., A.M., S.M., K.T., T.N., T. Takahashi, T. Tatsumi, H.M.) and Pharmacology (K.M.), Kyoto Prefectural University of Medicine; and Department of Pathology (Y.A.), Kansai Medical University, Osaka, Japan.

Correspondence to Mitsuhiko Okigaki, MD, Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail okigakim{at}koto.kpu-m.ac.jp

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 ß-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.

Key Words: restenosis • endothelium • progenitor cells • erythropoietin

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