1,25(OH)₂D₃ improves diabetic wound healing by modulating inflammation and promoting angiogenesis

Vitamin D was found to regulate inflammatory response and angiogenesis, which were often impaired in diabetic wound healing. This study aimed to investigate the effects of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] on diabetic wound healing both in vivo and in vitro. Diabetes was induced by high-fat diet combined with streptozotocin. After four weeks of establishing diabetic mouse model, full-thickness excisional wounds were created on their dorsal skin. Then 1,25(OH)₂D₃ was administered via intraperitoneal injection for 14 consecutive days. Human umbilical vein endothelial cells (HUVECs) were cultured with normal glucose, high glucose, high glucose plus 1,25(OH)₂D₃. Cell proliferation, migration, tube formation, and expression levels of relevant pathway components were measured. Intervention with 1,25(OH)₂D₃ significantly increased wound closure rates of diabetic mice. During the inflammatory phase, 1,25(OH)₂D₃ alleviated excessive inflammation and promoted the transition of macrophages from M1 to M2 phenotype. Regarding vascular endothelial function, 1,25(OH)₂D₃ significantly up-regulated eNOS protein expression and inhibited Vcam-1 mRNA expression in diabetic mice (P < 0.05). As for angiogenesis, 1,25(OH)₂D₃ markedly increased CD31-positive area, the protein and mRNA expression of VEGF, VEGFR2, PDGF, and PDGFRβ, as well as the mRNA expression of Bfgf and Egfr (P < 0.05). In vitro, 1,25(OH)₂D₃ restored impaired cell proliferation, migration, and tube formation induced by high-glucose, and up-regulated expression of angiogenesis-related factors. These protective effects might be mediated through PI3K/AKT/HIF-1α pathway. These findings suggested that 1,25(OH)₂D₃ accelerated diabetic wound healing by modulating inflammation, restoring vascular endothelial dysfunction, and promoting angiogenesis.