Notch signaling regulates endothelial progenitor cell activity during recovery from arterial injury in hypercholesterolemic mice.
Notch signaling regulates endothelial progenitor cell activity during recovery from arterial injury in hypercholesterolemic mice.
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DOI：
10.1161/circulationaha.105.553917
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发表时间：
2010-03-09
期刊：
影响因子：
37.8
通讯作者：
Losordo DW
中科院分区：
文献类型：
--
作者：
Ii M;Takeshita K;Ibusuki K;Luedemann C;Wecker A;Eaton E;Thorne T;Asahara T;Liao JK;Losordo DW
内皮祖细胞（EPCs）在动脉粥样硬化中的作用知之甚少。因此，我们对高胆固醇血症（ApoE−/−）和野生型（WT）小鼠进行了一系列评估，以评估胆固醇如何影响动脉损伤后的再内皮化、动脉粥样硬化和EPC功能。出乎意料的是，ApoE−/−小鼠的再内皮化（通过对埃文斯蓝染色的抗性来评估）和循环EPC计数（EPC培养试验）比WT小鼠更高，ApoE−/−骨髓移植（BM）在WT小鼠中加速了内皮细胞的恢复，增加了BM来源的EPCs向新内皮细胞的募集。胆固醇浓度依赖性促进ApoE−/−和WT EPCs的增殖（MTS实验），而EPC粘附（对玻璃体连接蛋白、I型胶原、纤维连接蛋白和层粘连蛋白包被板）、迁移（改良Boyden - s-chamber实验）和抗凋亡（TUNEL染色）活性的浓度依赖性是双相的。胆固醇增强ApoE−/−和WT EPCs中血管内皮生长因子mRNA的表达（定量、实时RT-PCR），抑制Notch1 mRNA的表达；而ApoE−/−EPCs中eNOS mRNA表达增加，WT EPCs中eNOS mRNA表达下降。Notch1+/ - EPCs中的EPC活性高于WT EPCs， Notch1+/ - BM移植加速了WT小鼠动脉损伤后内皮细胞的恢复。本文的研究结果为内皮祖细胞在动脉粥样硬化中的作用提供了新的见解，并表明胆固醇和Notch1可能参与了内皮祖细胞活性的调节。
Little is known about the role of endothelial progenitor cells (EPCs) in atherosclerosis. Accordingly, we performed a series of assessments with hypercholesterolemic (ApoE−/−) and wild type (WT) mice to evaluate how cholesterol influences re-endothelialization, atherosclerosis, and EPC function after arterial injury. Unexpectedly, re-endothelialization (assesed via resistance to Evans blue staining) and circulating EPC counts (EPC-culture assay) were greater in ApoE−/− mice than in WT mice, and transplantation of ApoE−/− bone marrow (BM) in WT mice accelerated endothelial recovery and increased recruitment of BM-derived EPCs to the neo-endothelium. Cholesterol concentration-dependently promoted the proliferation (MTS assay) of both ApoE−/− and WT EPCs, and the concentration dependence of EPC adhesion (to vitronectin-, collagen type I-, fibronectin-, and laminin-coated plates), migration (modified Boyden's-chamber assay), and anti-apoptotic (TUNEL staining) activity was biphasic. Cholesterol enhanced the mRNA expression (quantitative, real-time RT-PCR) of vascular endothelial growth factor and inhibited Notch1 mRNA expression in both ApoE−/− and WT EPCs; whereas eNOS mRNA expression increased in ApoE−/− EPCs and declined in WT EPCs after cholesterol exposure. EPC activity was greater in Notch1+/– EPCs than in WT EPCs, and transplantation of Notch1+/– BM accelerated endothelial recovery after arterial injury in WT mice. The results presented here provide novel insights into the role of EPCs during atherosclerosis and suggest that cholesterol and Notch1 may be involved in the regulation of EPC activity.