Granulocyte colony-stimulating factor-mobilized circulating c-Kit+/Flk-1+progenitor cells regenerate endothelium and inhibit neointimal hyperplasia after vascular injury
Granulocyte colony-stimulating factor-mobilized circulating c-Kit+/Flk-1+progenitor cells regenerate endothelium and inhibit neointimal hyperplasia after vascular injury
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DOI：
10.1161/01.atv.0000205607.98538.9a
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发表时间：
2006-04-01
影响因子：
8.7
通讯作者：
Matsubara, H
中科院分区：
文献类型：
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作者：
Takamiya, M;Okigaki, M;Matsubara, H
背景-粒细胞集落刺激因子（G-CSF）治疗显示可抑制球囊损伤血管的新生内膜形成，然而，既没有用骨髓（BM）移植实验鉴定参与G-CSF介导的内皮再生的祖细胞，也没有研究再生内皮的功能特性。在大鼠颈动脉中，从球囊损伤前3天开始，每天注射（100 μ g/kg/天），持续14天。G-CSF可明显抑制14天裸血管内膜增生（39% vs对照组，P < 0.05）。内皮细胞特异性免疫染色显示再内皮化增强（相对于对照增加1.8倍; P < 0.05）和伊文思蓝染料外渗抑制（47%; P = 0.02）。再生的内皮细胞表现出乙酰胆碱介导的血管扩张NO依赖性的方式。G-CSF增加循环c-Kit+/Flk-1+细胞（9.1倍; P < 0.02），其在体外显示内皮特性（乙酰化低密度脂蛋白摄取和凝集素结合）并在体内掺入再生内皮。用过表达绿色荧光蛋白（GFP）的细胞进行的BM替代实验显示，BM来源的GFP+/CD 31+内皮细胞在G-CSF介导的新内皮细胞中占据总管腔长度的39结论-G-CSF诱导的BM衍生的c-Kit+/Flk-1+细胞的动员有助于内皮再生，这种细胞因子疗法可能是促进血管成形术后再内皮化的可行策略。
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 mu g/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.