The Role Of MiR-129-1-3p And MiR-214-3p In Cyclic Stretch-induced Endothelial Progenitor Cell Differentiation

Endothelial progenitor cells(EPCs)are vital to the recovery of endothelial function and maintenance of vascular homeostasis through mobilizing to the sites of vessel injury and differentiating into mature endothelial cells(ECs).Once the tissue is damaged,bone marrow(BM)derived EPCs are recruited and migrate to the injury sites.EPCs are exposed to cyclic stretch imposed by blood flow,which plays important roles in modulating differentiation of EPCs.MicroRNAs(miRNAs)have emerged as key regulators of several cellular processes.However,the role of miRNAs in EPC differentiation induced by cyclic stretch is still unclear.BM-derived EPCs were exposed to cyclic stretch with the magnitude of 5%,which mimics the physiological stretch,at a constant frequency of 1.25 Hz for 24 hr.miRNAs array was performed to identify the expression profiling of miRNAs regulated by mechanical stretch.Here we set out to investigate the effects of microRNA-129-1-3p(miR-129-1-3p)and microRNA-214-3p(miR-214-3p).The results indicated that cyclic stretch significantly decreased miR-129-1-3p expression and induced EPC differentiation toward ECs,depressed EPC differentiation toward vascular smooth muscle cells(VSMCs).Runt-related transcription factor 2(Runx2),a putative target gene of miR-129-1-3p,was predicted by TargetScan(http://www.targetscan.org)and miRanda(http://www.microrna.org).Runx2,was increased by cyclic stretch.Dual luciferase reporter assay validated Runx2 as a direct target of miR-129-1-3p.Furthermore,siRNA-mediated knockdown of Runx2 inhibited EPC differentiation into ECs and attenuated tube formation of EPCs by modulating vascular endothelial growth factor(VEGF)secretion from EPCs in vitro.Furthermore,cyclic stretch depresses the expression of miR-214-3p significantly,enhance EPC proliferation and inhibits EPC differentiation towards VSMCs.Our findings demonstrated that physiological cyclic stretch regulates the expression of miRs and their target genes,which in turn promote endothelial differentiation of EPCs,proliferation and angiogenic ability.Thus,targeting key miRs may be a potential therapeutic strategy for treating vessel injury.