Hyperglycemia Interacts with Ischemia in a Synergistic Way on Wound Repair and Myofibroblast Differentiation.

Diabetes mellitus is the most important factor predisposing to chronic wounds.1 Up to 25% of patients with diabetes develop a chronic ulcer during their lifetime,2,3 which is associated with significantly reduced life quality4 and greatly increased mortality.5,6 Chronic ulcers often require long-term and expensive therapy imposing a staggering burden on the public health systems.7,8 Current theories about the physiopathology of diabetic foot ulcers emphasize the importance of the classical triad of ischemia due to angiopathy, neuropathy, and infection.9,10 By contrast, the role of hyperglycemia per se is not well elucidated and remains controversial.3,11,12 Clinical studies reported that hyperglycemia may interfere with ischemia and adversely affect the outcome of ischemic insults,13–17 but this interaction has not been investigated in wound repair yet. During wound repair, local dermal fibroblasts and precursor cells from other sources differentiate into myofibroblasts by neoexpressing α-smooth muscle actin (α-SMA), conferring to them high contractile activity18,19 and promoting wound contraction.20 We previously demonstrated that ischemic wounds exhibit decreased levels of myofibroblast appearance and α-SMA expression with consequently a prolonged repair time.21,22 To date, there is no appropriate experimental model to specifically study the interaction between hyperglycemia and ischemia in the setting of wound repair. To address this question, we have developed an animal wound model designed to investigate ischemic wound repair in both normoglycemic and streptozotocin-induced hyperglycemic rats. Because ischemia was previously shown to impede myofibroblast differentiation,22 we particularly focused on the behavior of these cells. In this study, we aimed to investigate the role of hyperglycemia on wound healing and whether hyperglycemia per se amplifies the negative effects of ischemia.