Insulin-like growth factor-1 (IGF-1) decreases atherosclerosis in Apolipoprotein E (Apoe) -deficient mice when administered systemically. However, mechanisms for its atheroprotective effect are not fully understood. We generated endothelium-specific IGF-1 receptor (IGF1R) deficient mice on Apoe-deficient background to assess effects of IGF-1 on the endothelium in the context of hyperlipidemia-induced atherosclerosis. Endothelial deficiency of IGF1R promoted atherosclerotic burden, when animals were fed on high-fat diet for 12 weeks or normal chow for 12 months. Under normal chow feeding condition, the vascular relaxation response to acetylcholine was increased in endothelial IGF1R deficient aorta, however high-fat diet feeding substantially attenuated the relaxation response and there was no difference between endothelial IGF1R deficient and control mice. The endothelium and its intercellular junctions provide a barrier function to the vasculature. In human aortic endothelial cells, IGF-1 upregulated occludin, claudin 5, VE-cadherin, JAM-A, and CD31 expression levels, and vice versa, specific IGF1R inhibitor, PPP, an IGF1R neutralizing antibody (αIR3) or siRNA to IGF1R abolished the IGF-1 effects on junction and adherens proteins, suggesting that IGF-1 promoted endothelial barrier function. Accordingly, occludin and claudin 5 were downregulated in IGF1R-deficient mouse aorta. Moreover, endothelial transwell permeability assays indicated that inhibition of IGF-1 signaling elevated solute permeability through the monolayer of human aortic endothelial cells. In summary, endothelial IGF1R deficiency increases atherosclerosis and IGF-1 positively regulates tight- and adherens junction protein levels and endothelial barrier function. Our findings suggest that the elevation of endothelial junction protein level is, at least in part, the mechanism for anti-atherogenic effects of IGF-1.

中文翻译：

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胰岛素样生长因子-1受体的内皮缺乏会降低Apoe缺陷小鼠的内皮屏障功能并促进动脉粥样硬化。

当全身给药时，胰岛素样生长因子-1 (IGF-1) 可降低载脂蛋白 E (Apoe) 缺陷小鼠的动脉粥样硬化。然而，其动脉粥样硬化保护作用的机制尚不完全清楚。我们在 Apoe 缺陷背景下生成内皮特异性 IGF-1 受体 (IGF1R) 缺陷小鼠，以评估 IGF-1 在高脂血症诱导的动脉粥样硬化背景下对内皮的影响。当动物以高脂饮食喂养 12 周或正常食物喂养 12 个月时，IGF1R 的内皮缺乏会增加动脉粥样硬化的负担。在正常食物喂养条件下，内皮IGF1R缺陷主动脉血管对乙酰胆碱的松弛反应增加，然而，高脂肪饮食喂养显着减弱了放松反应，并且内皮 IGF1R 缺陷小鼠和对照小鼠之间没有差异。内皮及其细胞间连接为脉管系统提供屏障功能。在人主动脉内皮细胞中，IGF-1 上调 occludin、claudin 5、VE-cadherin、JAM-A 和 CD31 的表达水平，反之亦然，特异性 IGF1R 抑制剂 PPP、IGF1R 中和抗体 (αIR3) 或 IGF1R 的 siRNA 被取消IGF-1 对连接蛋白和粘附蛋白的影响，表明 IGF-1 促进了内皮屏障功能。因此，在 IGF1R 缺陷小鼠主动脉中，occludin 和 claudin 5 被下调。而且，内皮 transwell 通透性测定表明，抑制 IGF-1 信号传导可提高通过人主动脉内皮细胞单层的溶质通透性。总之，内皮IGF1R缺乏会增加动脉粥样硬化，而IGF-1正向调节紧密连接蛋白水平和内皮屏障功能。我们的研究结果表明，内皮连接蛋白水平的升高至少部分是 IGF-1 抗动脉粥样硬化作用的机制。