Upregulation of miRNA-106a-5p delays diabetic wound healing through reducing the expression of TIMP2 of vascular endothelial cells.

Abstract

Diabetic wounds (DWs) are characterized by impaired angiogenesis, which is a key factor contributing to delayed wound healing. However, the specific regulators of angiogenic dysfunction in DWs remain poorly understood. In this study, we identified the abnormal downregulation of tissue inhibitor of metalloproteinases 2 (TIMP2) in skin wounds of diabetic patients through RNA sequencing and histopathological techniques. By upregulating TIMP2 expression via adeno-associated virus (AAV) transfection in vitro and in vivo, we demonstrated that TIMP2 overexpression enhanced vascular endothelial cell proliferation through activation of the PI3K-AKT signaling pathway and promoted wound healing in diabetic mice. Furthermore, using multiple online functional prediction databases and dual luciferase reporter assays, we investigated miR-106a-5p as an upstream regulator of TIMP2, which was upregulated in the wounds of diabetic mice. Inhibition of miR-106a-5p can upregulate TIMP2 mRNA expression in vascular endothelial cells, leading to increased cell proliferation and decreased apoptosis, thereby accelerating wound healing in diabetic mice. Our findings underscore the critical role of the TIMP2 and its upstream regulator miR-106a-5p in angiogenesis during wound healing, providing a promising avenue for diabetic wound repair.