OBJECTIVE MicroRNA-126-3p (miR-126) is required for angiogenesis during organismal development or the repair of injured arterial vasculature. The role of miR-126 in lung microvascular endothelial cells, which are essential for gas exchange and for lung injury repair and regeneration, remains poorly understood. Considering the significant heterogeneity of endothelial cells from different vascular beds, we aimed to determine the role of miR-126 in regulating lung microvascular endothelial cell function and to elucidate its downstream signaling pathways. Approach and Results: Overexpression and knockdown of miR-126 in primary human lung microvascular endothelial cells (HLMVEC) were achieved via transfections of miR-126 mimics and antisense inhibitors. Increasing miR-126 levels in HLMVEC reduced cell proliferation, weakened tube formation, and increased cell apoptosis, whereas decreased miR-126 levels stimulated cell proliferation and tube formation. Whole-genome RNA sequencing revealed that miR-126 was associated with an antiangiogenic and proapoptotic transcriptomic profile. Using validation assays and knockdown approaches, we identified that the effect of miR-126 on HLMVEC angiogenesis was mediated by the LAT1 (L-type amino acid transporter 1), via regulation of mTOR (mammalian target of rapamycin) signaling. Furthermore, downregulation of miR-126 in HLMVEC inhibited cell apoptosis and improved endothelial tube formation during exposure to environmental insults such as cigarette smoke. CONCLUSIONS miR-126 inhibits HLMVEC angiogenic function by targeting the LAT1-mTOR signaling axis, suggesting that miR-126 inhibition may be useful for conditions associated with microvascular loss, whereas miR-126 augmentation may help control unwanted microvascular angiogenesis.

中文翻译：

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MicroRNA-126-3p通过LAT1（L型氨基酸转运蛋白1）介导的mTOR（雷帕霉素的哺乳动物靶标）信号传导抑制人肺微血管内皮细胞的血管生成功能。

目的MicroRNA-126-3p（miR-126）是机体发育或受损动脉血管系统修复过程中血管生成所必需的。对于气体交换以及肺损伤修复和再生必不可少的miR-126在肺微血管内皮细胞中的作用仍然知之甚少。考虑到来自不同血管床的内皮细胞的显着异质性，我们旨在确定miR-126在调节肺微血管内皮细胞功能中的作用并阐明其下游信号传导途径。方法和结果：通过转染miR-126模拟物和反义抑制剂，实现了原代人肺微血管内皮细胞（HLMVEC）中miR-126的过表达和敲低。HLMVEC中miR-126水平的升高会降低细胞增殖，削弱管的形成，细胞凋亡增加，而miR-126水平降低则刺激细胞增殖和管形成。全基因组RNA测序显示miR-126与抗血管生成和促凋亡转录组谱相关。使用验证分析和敲低方法，我们确定了miR-126对HLMVEC血管生成的影响是通过调节mTOR（雷帕霉素的哺乳动物靶标）信号转导而由LAT1（L型氨基酸转运蛋白1）介导的。此外，HLMVEC中miR-126的下调抑制了细胞暴露于环境损害（例如香烟烟雾）中的细胞凋亡并改善了内皮管的形成。结论miR-126通过靶向LAT1-mTOR信号轴来抑制HLMVEC血管生成功能，