Transient High Glucose Causes Persistent Vascular Dysfunction and Delayed Wound Healing by the DNMT1-Mediated Ang-1/NF-κB Pathway

The progression of diabetic complications does not halt despite the termination of hyperglycemia, suggesting a metabolic memory phenomenon. However, whether metabolic memory exists in and affects the healing of diabetic wounds, as well as the underlying molecular mechanisms, remain unclear. In this study, we found that wound healing was delayed, and angiogenesis was decreased in mice with diabetes despite the normalization of glycemic control. Thus, we hypothesized that transient hyperglycemic spikes may be a risk factor for diabetic wound healing. We showed that transient hyperglycemia caused persistent damage to the vascular endothelium. Transient hyperglycemia directly upregulated DNMT1 expression, leading to the hypermethylation of Ang-1 and reduced Ang-1 expression, which in turn induced long-lasting activation of NF-kappa B and subsequent endothelial dysfunction. An in vivo study further showed that inhibition of DNMT1 promoted angiogenesis and accelerated diabetic wound healing by regulating the Ang-1/NF-kappa B signaling pathway. These results highlight the dramatic and long-lasting effects of transient hyperglycemic spikes on wound healing and suggest that DNMT1 is a target for diabetic vascular complications.