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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:751.)
© 2006 American Heart Association, Inc.

Vascular Biology

Granulocyte Colony-Stimulating Factor–Mobilized Circulating c-Kit+/Flk-1+ Progenitor Cells Regenerate Endothelium and Inhibit Neointimal Hyperplasia After Vascular Injury

Michitaka Takamiya; Mitsuhiko Okigaki; Denan Jin; Shinji Takai; Yoshihisa Nozawa; Yasushi Adachi; Norifumi Urao; Kento Tateishi; Tetsuya Nomura; Kan Zen; Eishi Ashihara; Mizuo Miyazaki; Tetsuya Tatsumi; Tomosaburo Takahashi; Hiroaki Matsubara

From the Department of Cardiovascular Medicine (M.T., M.O., N.U., K.T., T.N., K.Z., E.A., T. Tatsumi, T. Takahashi, H.M.), Kyoto Prefectural University School of Medicine, Japan; Department of Pharmacology (D.J., S.T., M.M.), Osaka Medical College, Takatsuki, Japan; Pharmacobioregulation Research Laboratory (Y.N.), Taiho Pharmaceutical Co. Ltd, Saitama, Japan; and Department of Pathology II (Y.A.), Kansai Medical University, Moriguchi, 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

Background— Granulocyte colony-stimulating factor (G-CSF) treatment was shown to inhibit neointimal formation of balloon-injured vessels, whereas neither the identification of progenitor cells involved in G-CSF–mediated endothelial regeneration with a bone marrow (BM) transplant experiment nor the functional properties of regenerated endothelium have been studied.

Methods and Results— Recombinant human G-CSF (100 µg/kg per day) was injected daily for 14 days starting 3 days before balloon injury in the rat carotid artery. Neointimal formation of denuded vessels on day 14 was markedly attenuated by G-CSF (39% versus the control; P<0.05). Endothelial cell–specific immunostaining revealed an enhancement of re-endothelialization (1.8-fold increase versus the control; P<0.05) and inhibition of extravasation of Evans Blue dye (47%; P=0.02). The regenerated endothelium exhibited acetylcholine-mediated vasodilatation in NO-dependent manner. G-CSF increased the circulating c-Kit+/Flk-1+ cells (9.1-fold; P<0.02), which showed endothelial properties in vitro (acetylated low-density lipoprotein uptake and lectin binding) and incorporated into the regenerated endothelium in vivo. A BM replacement experiment with green fluorescent protein (GFP)–overexpressing cells showed that BM-derived GFP+/CD31+ endothelial cells occupied 39% of the total luminal length in the G-CSF–mediated neo-endothelium (2% in the control).

Conclusion— The G-CSF–induced mobilization of BM-derived c-Kit+/Flk-1+ cells contributes to endothelial regeneration, and this cytokine therapy may be a feasible strategy for the promotion of re-endothelialization after angioplasty.

Subcutaneous injection of G-CSF increases in re-endothelialization of the denuded vessels, followed by inhibition of neointimal formation. The G-CSF–induced endothelium exhibited normal acetylcholine-mediated vasodilatation in NO-dependent manner. Bone marrow (BM) replacement by GFP-overexpressing cells showed that G-CSF–mobilized Lin-/c-Kit+/Flk-1+ cells from BM contributes to endothelial regeneration.

Key Words: restenosis • endothelium • carotid artery • cytokines • vascular biology

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