MicroRNA-100 Regulates Neovascularization by Suppression of Mammalian Target of Rapamycin in Endothelial and Vascular Smooth Muscle Cells
MicroRNA-100 Regulates Neovascularization by Suppression of Mammalian Target of Rapamycin in Endothelial and Vascular Smooth Muscle Cells
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DOI：
10.1161/circulationaha.110.000323
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发表时间：
2011-03-08
期刊：
影响因子：
37.8
通讯作者：
Moser, Martin
中科院分区：
文献类型：
--
作者：
Grundmann, Sebastian;Hans, Felix P.;Moser, Martin
背景-血管的适应性生长是心血管疾病的重要保护机制。然而，这一过程的基本调控机制只有部分了解。近年来，研究发现内源性小分子RNA（microRNA [miRNAs]）在胚胎和出生后血管发育中起重要作用。在这里，我们使用miRNA转录组分析诱导小鼠后肢缺血后筛选参与适应性血管生长的miRNA以下arterial occlusion.Methods and Results-Using miRNA arrays，我们探讨了适应性新生血管形成过程中的miRNA表达谱。我们描述了miRNA表达模式的特定变化，并表明在小鼠后肢缺血诱导后，miRNA-100显著下调。我们的数据表明，miR-100调节内皮细胞的增殖、管形成和发芽活性以及血管平滑肌细胞的迁移，并作为丝氨酸/苏氨酸蛋白激酶哺乳动物雷帕霉素靶蛋白（mTOR）的内源性阻遏物发挥作用。而miR-100抑制增加了内皮细胞中的mTOR水平，miR-100的过表达减少了mTOR表达，从而减弱了细胞增殖。支持这一观点的是，缺乏miRNA结合位点的mTOR构建体的过表达挽救了miR-100对细胞增殖的抑制作用。因此，在小鼠中，通过特异性miR-100抑制剂在体内刺激血管生成并导致股动脉闭塞后灌注的功能改善。与此相反，治疗与mTOR抑制剂雷帕霉素有相反的effects. Conclusions，我们的数据表明，miR-100具有抗血管生成功能，并抑制mTOR信号在内皮细胞和血管平滑肌细胞。抑制miR-100可能是调节血管生长和其他mTOR依赖性过程的新方法。（循环。2011; 123：999-1009）。
Background-The adaptive growth of blood vessels is an important protective mechanism in cardiovascular disease. However, the underlying regulatory mechanisms of this process are only partly understood. Recently, small endogenous RNAs (microRNAs [miRNAs]) were found to play an important role in embryonic and postnatal vascular development. Here, we used miRNA transcriptome analysis after induction of hind-limb ischemia in mice to screen for miRNAs involved in adaptive blood vessel growth following arterial occlusion.Methods and Results-Using miRNA arrays, we explored the miRNA expression profile during adaptive neovascularization. We describe specific changes in miRNA expression patterns and show that miRNA-100 is significantly downregulated after induction of hind-limb ischemia in mice. Our data demonstrate that miR-100 modulates proliferation, tube formation, and sprouting activity of endothelial cells and migration of vascular smooth muscle cells and functions as an endogenous repressor of the serine/threonine protein kinase mammalian target of rapamycin (mTOR). Whereas miR-100 inhibition increased mTOR levels in endothelial cells, overexpression of miR-100 reduced mTOR expression and consequently attenuated cellular proliferation. Supporting this notion, overexpression of an mTOR construct lacking the miRNA binding site rescued the inhibitory effect of miR-100 on cell proliferation. Accordingly, miR-100 inhibition by specific antagomirs in vivo stimulated angiogenesis and resulted in functional improvement of perfusion after femoral artery occlusion in mice. In contrast, treatment with the mTOR inhibitor rapamycin had the opposite effect.Conclusions-Our data demonstrate that miR-100 has an antiangiogenic function and represses mTOR signaling in endothelial and vascular smooth muscle cells. Inhibition of miR-100 could be a novel approach for the modulation of blood vessel growth and other mTOR-dependent processes. (Circulation. 2011; 123: 999-1009.)