Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia
Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia
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DOI：
10.1161/01.res.0000224117.59417.f3
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发表时间：
2006-06-09
影响因子：
20.1
通讯作者：
Matsubara, Hiroaki
中科院分区：
文献类型：
--
作者：
Urao, Norifumi;Okigaki, Mitsuhiko;Matsubara, Hiroaki
我们研究了外源性促红细胞生成素（Epo）动员内皮祖细胞（EPCs）是否促进损伤内皮的修复。在小鼠股动脉线损伤后注射重组人Epo（1000 IU/kg，最初3天）。Epo对新生内膜形成的抑制作用为对照组的48%（P < 0.05），且呈NO依赖性。Epo诱导第14天裸露血管的再内皮化面积增加1.4倍，其中55%来自骨髓（BM）细胞。Epo依赖性地增加了循环中Sca-1（+）/Flk-1（+）EPCs的数量（2.0倍，P < 0.05）。用GFP或β-半乳糖苷酶过表达的细胞替代BM表明，Epo刺激BM衍生的EPCs的分化和常驻EC的增殖。在Epo诱导的新生内皮中，BM来源的EC增加2.2- 2.7倍（P < 0.05），其中Epo受体的表达上调。Epo诱导EPCs Akt/eNOS磷酸化和NO合成，并对钢丝损伤的动脉产生抗凋亡作用。总之，Epo治疗以NO依赖的方式抑制动脉损伤后的新生内膜增生，其作用于损伤的血管并动员EPCs到新生内皮。
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.