Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, UK.
Diabetes. 2012 Sep;61(9):2359-68. doi: 10.2337/db11-1494. Epub 2012 Jun 25.
We recently demonstrated that reducing IGF-1 receptor (IGF-1R) numbers in the endothelium enhances nitric oxide (NO) bioavailability and endothelial cell insulin sensitivity. In the present report, we aimed to examine the effect of increasing IGF-1R on endothelial cell function and repair. To examine the effect of increasing IGF-1R in the endothelium, we generated mice overexpressing human IGF-1R in the endothelium (human IGF-1R endothelium-overexpressing mice [hIGFREO]) under direction of the Tie2 promoter enhancer. hIGFREO aorta had reduced basal NO bioavailability (percent constriction to N(G)-monomethyl-l-arginine [mean (SEM) wild type 106% (30%); hIGFREO 48% (10%)]; P < 0.05). Endothelial cells from hIGFREO had reduced insulin-stimulated endothelial NO synthase activation (mean [SEM] wild type 170% [25%], hIGFREO 58% [3%]; P = 0.04) and insulin-stimulated NO release (mean [SEM] wild type 4,500 AU [1,000], hIGFREO 1,500 AU [700]; P < 0.05). hIGFREO mice had enhanced endothelium regeneration after denuding arterial injury (mean [SEM] percent recovered area, wild type 57% [2%], hIGFREO 47% [5%]; P < 0.05) and enhanced endothelial cell migration in vitro. The IGF-1R, although reducing NO bioavailability, enhances in situ endothelium regeneration. Manipulating IGF-1R in the endothelium may be a useful strategy to treat disorders of vascular growth and repair.
我们最近证明，减少内皮细胞中的 IGF-1 受体 (IGF-1R) 数量可以提高一氧化氮 (NO) 的生物利用度和内皮细胞对胰岛素的敏感性。在本报告中，我们旨在研究增加 IGF-1R 对内皮细胞功能和修复的影响。为了研究增加内皮细胞中的 IGF-1R 的影响，我们在 Tie2 启动子增强子的指导下，生成了内皮细胞中过表达人 IGF-1R 的小鼠（人 IGF-1R 内皮细胞过表达小鼠 [hIGFREO]）。hIGFREO 主动脉的基础 NO 生物利用度降低（平均（SEM）野生型 106%（30%）；hIGFREO 48%（10%）；P < 0.05）。hIGFREO 内皮细胞的胰岛素刺激内皮型一氧化氮合酶激活减少（平均（SEM）野生型 170%（25%），hIGFREO 58%（3%）；P = 0.04）和胰岛素刺激的 NO 释放减少（平均（SEM）野生型 4,500 AU（1,000），hIGFREO 1,500 AU（700）；P < 0.05）。hIGFREO 小鼠在动脉损伤后内皮再生增强（平均（SEM）恢复面积百分比，野生型 57%（2%），hIGFREO 47%（5%）；P < 0.05），体外内皮细胞迁移增强。IGF-1R 虽然降低了 NO 的生物利用度，但增强了原位内皮细胞再生。在内皮细胞中操纵 IGF-1R 可能是治疗血管生长和修复障碍的一种有用策略。
