Abstract
Diabetic foot ulcer (DFU) is a severe complication of diabetes, characterized by chronic, difficult‑to‑heal foot wounds. It has been hypothesized that miR‑222‑3p may influence wound healing via the regulation of angiogenesis. To elucidate the underlying mechanism, experimental investigations were conducted in vitro using human dermal microvascular endothelial cells (HMEC‑1) and in vivo in a mouse model of streptozotocin‑induced diabetes. Methylglyoxal (MGO), a glycolytic intermediate, is known to contribute to diabetic vascular complications. The results demonstrated that MGO‑treated HMEC‑1 cells exhibited an increased expression of miR‑222‑3p and impaired microvascular endothelial cell function. The overexpression of miR‑222‑3p in MGO‑treated HMEC‑1 cells further suppressed cell proliferation, migration and tube formation, while it enhanced apoptosis. Moreover, the upregulation of miR‑222‑3p reduced the expression of apelin (APLN), and dual‑luciferase reporter assays confirmed APLN as a direct downstream target of miR‑222‑3p. The silencing of APLN markedly impaired HMEC‑1 cell function. Notably, both the exogenous supplementation with Apelin‑13 and the overexpression of APLN significantly reversed endothelial dysfunction caused by the upregulation of miR‑222‑3p. In vivo, in both normal and diabetic mice, the elevated expression of miR‑222‑3p in skin wounds reduced APLN levels in the peri‑wound tissue and impaired wound healing. However, the overexpression of APLN or the inhibition of miR‑222‑3p with an antagomiR reversed this impairment. Collectively, these results suggest that miR‑222‑3p impairs microvascular endothelial cell function by targeting APLN, thereby contributing to delayed wound healing in diabetic skin.