miR-25-3p promotes endothelial cell angiogenesis in aging mice via TULA-2/SYK/VEGFR-2 downregulation

In aging, the regulation of angiogenesis is a dynamic and complex process. We aimed to identify and characterize microRNAs that regulate angiogenesis during aging. We showed that, in response to vascular endothelial senescence, microRNA-25-3p (miR-25-3p) plays the role of an angiogenic microRNA by targeting TULA-2 (T-cell ubiquitin ligand-2)/SYK (spleen tyrosine kinase)/VEGFR-2 (vascular endothelial growth factor receptor 2) signaling in vitro and in vivo. Mechanistic studies demonstrated that miR-25-3p inhibits a TULA-2/SYK/VEGFR-2 signaling pathway in endothelial cells. In old endothelial cells (OECs), upregulation of miR-25-3p inhibited the expression of TULA-2, which caused downregulation of the interaction between TULA-2 and SYK and increased phosphorylation of SYK Y323. The increased SYK Y323 phosphorylation level upregulated the phosphorylation of VEGFR-2 Y1175, which plays a vital role in angiogenesis, while miR-25-3p downregulation in YECs showed opposite effects. Finally, a salvage study showed that miR-25-3p upregulation promoted capillary regeneration and hindlimb blood flow recovery in aging mice with hindlimb ischemia. These findings suggest that miR-25-3p acts as an agonist of TULA-2/SYK/VEGFR-2 and mediates the endothelial cell angiogenesis response, which shows that the miR-25-3p/TULA-2 pathway may be potential therapeutic targets for angiogenesis during aging.