title: Erythropoietin-mobilized endothelial progenitors enhance reendothelialization via Akt-endothelial nitric oxide synthase activation and prevent neointimal hyperplasia.
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.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Urao
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Okigaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamada
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Aadachi
authors.forename: Kuniharu
authors.initials: K
authors.lastname: Matsuno
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsui
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Matsunaga
authors.forename: Kento
authors.initials: K
authors.lastname: Tateishi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nomura
authors.forename: Tomosaburo
authors.initials: T
authors.lastname: Takahashi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsubara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D004789:Enzyme Activation; D004921:Erythropoietin / Q000494:pharmacology*; D005263:Femoral Artery / Q000293:injuries / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011994:Recombinant Proteins; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*; D014945:Wound Healing / Q000187:drug effects*; D014947:Wounds and Injuries / Q000378:metabolism / Q000503:physiopathology
chemical_list: D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt