The results indicated that VEGF expression is regulated by HIF1α under hypoxia conditions, and the expression of either ERβ or SOD2, or ERβ agonist DPN treatment, diminishes hyperglycemia-induced persistent ROS generation, activates HIF1α transcriptional activity, and subsequently upregulates VEGF expression, favoring wound healing. Here, ESR2 is linked to Hyperglycemia.