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Circulation Research. 2006
Published online before print April 27, 2006, doi: 10.1161/01.RES.0000224117.59417.f3
A more recent version of this article appeared on June 9, 2006
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Submitted on November 28, 2005
Revised on March 22, 2006
Accepted on April 18, 2006

Erythropoietin-Mobilized Endothelial Progenitors Enhances Reendothelialization via Akt-Endothelial Nitric Oxide Synthase Activation and Prevents Neointimal Hyperplasia

Norifumi Urao ; Mitsuhiko Okigaki *; Hiroyuki Yamada ; Yasushi Aadachi ; Kuniharu Matsuno ; Akihiro Matsui ; Shinsaku Matsunaga ; Kento Tateishi ; Tetsuya Nomura ; Tomosaburo Takahashi ; Tetsuya Tatsumi ; and 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.

* To whom correspondence should be addressed. 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 {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.
Key words: restenosis • endothelium • progenitor cells • erythropoietin


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