Endothelial progenitor thrombospondin-1 mediates diabetes-induced delay in reendothelialization following arterial injury
Endothelial progenitor thrombospondin-1 mediates diabetes-induced delay in reendothelialization following arterial injury
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DOI：
10.1161/01.res.0000209948.50943.ea
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发表时间：
2006-03-17
影响因子：
20.1
通讯作者：
Losordo, DW
中科院分区：
文献类型：
--
作者：
Ii, M;Takenaka, H;Losordo, DW
延迟再内皮化导致糖尿病患者血管成形术和支架术后再狭窄。先前的数据表明，骨髓（BM）来源的内皮祖细胞（EPCs）有助于动脉损伤后的内皮恢复。我们研究了糖尿病患者EPC对再内皮化的贡献可能受损，导致再内皮化延迟的假设。在导丝诱导的颈动脉剥脱模型中，与非糖尿病小鼠相比，糖尿病小鼠的再内皮化显著减少。与非糖尿病小鼠相比，Tie 2/LacZ BM移植糖尿病小鼠中EPC对新内皮的贡献显着减少。将糖尿病小鼠和非糖尿病小鼠的骨髓移植到非糖尿病小鼠中，显示糖尿病骨髓受体的再内皮化受损。为了研究裸露动脉与内皮祖细胞在糖尿病中的相对作用，我们在糖尿病和非糖尿病小鼠动脉损伤后静脉注射糖尿病和非糖尿病内皮祖细胞。无论受体小鼠的糖尿病状态如何，糖尿病EPCs向新内皮的募集显著减少。在体外，糖尿病EPCs表现出降低迁移和粘附活动。血管内皮生长因子和内皮型一氧化氮合酶的表达也显着降低糖尿病EPCs。值得注意的是，血小板反应蛋白-1 mRNA表达在糖尿病EPCs中显著上调，与体外和体内EPC粘附活性降低相关。糖尿病中内皮祖细胞功能障碍会损害再内皮化。与非糖尿病EPCs相比，糖尿病EPCs具有涉及血小板反应蛋白-1表达的表型差异，揭示了改善糖尿病再内皮化和减少再狭窄的潜在新机制见解和治疗靶点。
Delayed reendothelialization contributes to restenosis after angioplasty and stenting in diabetes. Prior data have shown that bone marrow (BM)-derived endothelial progenitor cells (EPCs) contribute to endothelial recovery after arterial injury. We investigated the hypothesis that the EPC contribution to reendothelialization may be impaired in diabetes, resulting in delayed reendothelialization. Reendothelialization was significantly reduced in diabetic mice compared with nondiabetic mice in a wire-induced carotid denudation model. The EPC contribution to neoendothelium was significantly reduced in Tie2/LacZ BM-transplanted diabetic versus nondiabetic mice. BM from diabetic and nondiabetic mice was transplanted into nondiabetic mice, revealing that reendothelialization was impaired in the recipients of diabetic BM. To examine the relative roles of denuded artery versus EPCs in diabetes, we injected diabetic and nondiabetic EPCs intravenously after arterial injury in diabetic and nondiabetic mice. Diabetic EPCs recruitment to the neoendothelium was significantly reduced, regardless of the diabetic status of the recipient mice. In vitro, diabetic EPCs exhibited decreased migration and adhesion activities. Vascular endothelial growth factor and endothelial NO synthase expressions were also significantly reduced in diabetic EPCs. Notably, thrombospondin-1 mRNA expression was significantly upregulated in diabetic EPCs, associating with the decreased EPC adhesion activity in vitro and in vivo. Reendothelialization is impaired by malfunctioning EPCs in diabetes. Diabetic EPCs have phenotypic differences involving thrombospondin-1 expression compared with nondiabetic EPCs, revealing potential novel mechanistic insights and therapeutic targets to improve reendothelialization and reduce restenosis in diabetes.