Published online before print January 26, 2006, doi: 10.1161/01.ATV.0000205607.98538.9a
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© 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
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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