MicroRNA-129-1-3p regulates cyclic stretch-induced endothelial progenitor cell differentiation by targeting Runx2
MicroRNA-129-1-3p regulates cyclic stretch-induced endothelial progenitor cell differentiation by targeting Runx2
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MicroRNA-129-1-3p 通过靶向 Runx2 调节循环拉伸诱导的内皮祖细胞分化
DOI：
10.1002/jcb.27800
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发表时间：
2019-04-01
影响因子：
4
通讯作者：
Han, Yue
中科院分区：
文献类型：
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作者：
Li, Na;Wang, Wen-Bin;Han, Yue
内皮祖细胞（EPCs）对内皮功能的恢复和血管稳态的维持至关重要。内皮细胞被动员到血管损伤部位并分化为成熟的内皮细胞（ECs）。局部动员的EPCs暴露于血流引起的循环拉伸，这对EPCs分化很重要。MicroRNAs （miRNAs）已成为几个细胞过程的关键调节因子。然而，mirna在循环拉伸诱导的EPC分化中的作用尚不清楚。在这里，我们研究了microRNA‐129‐1‐3p （miR‐129‐1‐3p）及其新靶标Runt‐相关转录因子2 （Runx2）对循环拉伸诱导的EPC分化的影响。骨髓来源的EPCs在1.25 Hz的恒定频率下暴露于5%的循环拉伸（模拟生理机械应力）24小时。miRNA阵列结果显示，循环拉伸显著降低miR - 129 - 1 - 3p的表达。此外，我们发现miR - 129 - 1 - 3p在循环拉伸诱导的EPC向ECs分化过程中下调。同时，miR‐129‐1‐3p的靶基因Runx2的表达由于循环拉伸而增加。3'UTR报告基因试验证实Runx2是miR‐129‐1‐3p的直接靶标。此外，小干扰RNA （siRNA）介导的Runx2敲低抑制EPC向内皮细胞的分化，并通过调节内皮细胞的血管内皮生长因子（VEGF）分泌来减弱EPC管的形成。我们的研究结果表明，循环拉伸抑制miR - 129 - 1 - 3p的表达，进而激活Runx2和VEGF，促进内皮细胞分化和血管生成。因此，靶向miR‐129‐1‐3p和Runx2可能是治疗血管损伤的潜在治疗策略。
Endothelial progenitor cells (EPCs) are vital to the recovery of endothelial function and maintenance of vascular homeostasis. EPCs mobilize to sites of vessel injury and differentiate into mature endothelial cells (ECs). Locally mobilized EPCs are exposed to cyclic stretch caused by blood flow, which is important for EPC differentiation. MicroRNAs (miRNAs) have emerged as key regulators of several cellular processes. However, the role of miRNAs in cyclic stretch–induced EPC differentiation remains unclear. Here, we investigate the effects of microRNA‐129‐1‐3p (miR‐129‐1‐3p) and its novel target Runt‐related transcription factor 2 (Runx2) on EPC differentiation induced by cyclic stretch. Bone marrow‐derived EPCs were exposed to cyclic stretch with a magnitude of 5% (which mimics physiological mechanical stress) at a constant frequency of 1.25 Hz for 24 hours. The results from a miRNA array revealed that cyclic stretch significantly decreased miR‐129‐1‐3p expression. Furthermore, we found that downregulation of miR‐129‐1‐3p during cyclic stretch–induced EPC differentiation toward ECs. Meanwhile, expression of Runx2, a putative target gene of miR‐129‐1‐3p, was increased as a result of cyclic stretch. A 3′UTR reporter assay validated Runx2 as a direct target of miR‐129‐1‐3p. Furthermore, small interfering RNA (siRNA)‐mediated knockdown of Runx2 inhibited EPC differentiation into ECs and attenuated EPC tube formation via modulation of vascular endothelial growth factor (VEGF) secretion from EPCs in vitro. Our findings demonstrated that cyclic stretch suppresses miR‐129‐1‐3p expression, which in turn activates Runx2 and VEGF to promote endothelial differentiation of EPCs and angiogenesis. Therefore, targeting miR‐129‐1‐3p and Runx2 may be a potential therapeutic strategy for treating vessel injury.