Inhibition of miR-181c-5p Rescues Diabetes-Impaired Angiogenesis in Ischemia and Wound Healing

We found that patients with diabetic vascular complications have elevated circulating levels of miR-181c-5p, an antiangiogenic microRNA. We tested whether inhibition of miR-181c-5p increases angiogenesis in diabetic hindlimb ischemia and wound-healing models and elucidated its mechanisms of action. miR-181c-5p inhibition rescues diabetes-impaired ischemia-driven angiogenesis and wound healing and increases endothelial angiogenic capacity. This was concomitant with increases in VEGFA, VEGFR2, ERK2 phosphorylation, Bcl2, Elmo3, and Trib1. VEGFA is a likely direct target of miR-181c-5p, whereas ERK2, ELMO3, and TRIB1, although upregulated after miR-181c-5p inhibition, are indirectly regulated downstream. miR-181c-5p inhibition represents a promising therapeutic strategy for diabetic vascular complications.