Decreased miR‑92a‑3p expression potentially mediates the pro‑angiogenic effects of oxidative stress‑activated endothelial cell‑derived exosomes by targeting tissue factor
2020
Angiogenesis is an essential pathological feature of vulnerable atherosclerotic plaque. Exosomederived microRNAs (miRNAs or miRs) have been proven to be important regulators of angiogenesis. However, the role of exosomes, which are secreted by endothelial cells (ECs) under conditions of oxidative stress, in angiogenesis remain unclear. The present study aimed to investigate the effects and mechanism of oxidative stressactivated endothelialderived exosomes in angiogenesis. Exosomes were isolated from H2O2stimulated human umbilical vein ECs (HUVECs; termed Exo-H2O2) by differential centrifugation and characterized by transmission electron microscopy, nanoparticle tracking analysis and western blot analysis. Exo-H2O2 enhanced HUVEC proliferation, migration and tube formation, as determined by EdU incorporation assay, scratch wound migration assay and tube formation assay, respectively. miR92a3p was identified as the predominantly downregulated miRNA in the Exo-H2O2treated HUVECs by small RNA sequencing, and the expression of primary miR92a (primiR92a1) was also decreased, as shown by RTqPCR. Similarly, the inhibition of miR92a3p promoted angiogenesis in vitro and in vivo. miR92a3p overexpression blocked the proangiogenic effects of Exo-H2O2 on target ECs. Tissue factor (TF), a molecule involved in angiogenesis, was increased in HUVECs in which miR92a3p expression was downregulated, as shown by mRNA sequencing. TF was also predicted as a target of miR92a3p by using the RNAhybrid program. The overexpression or suppression of miR92a3p modified TF expression at both the mRNA and protein level, as measured by RTqPCR and western blot analysis, respectively. Luciferase reporter assays suggested that miR92a3p inhibited TF expression by binding to the 3' untranslated region of TF. On the whole, the findings of the present study demonstrate that exosomes released from oxidative stressactivated ECs stimulate angiogenesis by inhibiting miR92a3p expression in recipient ECs, and TF may be involved in the regulatory effects of miR92a3p on angiogenesis.
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