miR-765 induces angiogenesis by inhibiting dipeptidyl peptidase 4 and increasing fibroblast growth factor 2

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Given that extracellular vesicles (EVs) secreted from stem cells contain angiogenic microRNAs (miRNAs), these EVs show equivalent angiogenic therapeutic effect to cell transplantation. This study aimed to identify the angiogenic miRNAs from several miRNAs involved in EVs secreted from stem cells. In human dental pulp stem cells (hDPSCs) under hypoxic culture, vascular endothelial growth factor (VEGF) involved in EVs increased. We hypothesized that angiogenic miRNAs increase in EVs that are secreted from hDPSCs under hypoxic culture compared with those under normoxic culture. In the first screening, the expression levels of miRNAs involved in EVs that were secreted from hDPSCs cultured under hypoxic and normoxic conditions were analyzed using miRNA array. In the second screening, 12 miRNAs were individually involved in EVs, and the growth of human aortic endothelial cells was assayed. In the third screening, miRNA-encapsulated EVs were injected in BALB/c mouse hindlimb ischemia model, followed by angiogenesis evaluation by blood flow analysis. Results showed that miR-765 is an angiogenic miRNA, targeting the 3' untranslated region of dipeptidyl peptidase 4 (DPP4) and upregulating fibroblast growth factor 2 (FGF2) in vitro and in vivo. In conclusion, as an angiogenesis mechanism, miR-765 increased FGF2 expression levels by inhibiting DPP4.

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