Transient exposure to elevated glucose levels causes persistent changes in dermal microvascular endothelial cell responses to injury

BACKGROUND: The purpose of this study was to determine whether elevated glucose can induce a dermal microvascular endothelial cell metabolic memory, thus affecting angiogenesis in the repair process of mammalian cutaneous wound. We hypothesized that transient elevated glucose levels cause sustained alteration of endothelial cell responses to injury and persistent epigenetic changes in gene expression. METHODS: Human dermal microvascular endothelial cells were exposed to experimental conditions with or without 30 mM D-glucose. The control group was maintained at 5 mM D-glucose; while in the transient glucose group, after being exposed to 30 mM D-glucose for two days, then being put under the control conditions during the experiment. Besides, in the whole process of the experiment, the chronic glucose group was kept in the condition with 30 mM D-glucose. Proliferation, migration, tube formation, gene expression and histone methylation were assessed for individual conditions. RESULTS: Transient elevated glucose caused sustained effects on endothelial cell migration, tube formation and TIMP3 gene expression. The effects on TIMP3 expression were associated with persistent changes in histone modification at the 5' end of the TIMP3 gene, suggesting an epigenetic effect. CONCLUSIONS: Hyperglycemia induced metabolic memory could promote the regulation of TIMP3, and it can be used as a possible innovative molecular target for therapeutic intervention in the treatment of chronic non-healing diabetic wounds.