Objective: Diabetic patients show poor endothelial progenitor cell (EPC) functions and are prone to ischemic micro-vascular or macro-vascular complications. Melatonin has been shown to have protective effects in ischemic injury, possibly in part by modulating the functioning of EBCs. We investigated whether pretreatment with melatonin can restore the impaired functions of EPCs in diabetes.

Methods: Human EPC were isolated and cultured in a high-glucose medium for functional testing. Cell proliferation, nitric oxide (NO) production, and apoptosis assay were examined. A streptozocin (STZ)-induced diabetic mouse model was established to evaluate the actions of chronic hyperglycemia on ischemia-induced blood flow recovery. The circulating EPC number in the peripheral blood was determined by flow cytometry (Sca-1+/Flk-1+).

Results: Incubation with a high-glucose medium (25 mM) significantly suppressed EPC proliferation, reduced NO production, and lessened phosphorylations of Akt and eNOS. Moreover, EPC treated with high-glucose medium increased reactive oxygen species production, promoted cellular apoptosis and senescence, and also inhibited EPC tube formation. Treatment of melatonin could recover these harmful effects. Four weeks after hindlimb ischemia surgery, the STZ-induced diabetic mice had significantly reduced tissue reperfusion, EPC mobilization, and impaired neovascularization in the ischemic hindlimbs compared with the nondiabetic mice. In STZ-induced diabetic mice, the melatonin group showed significantly increased ischemic/non-ischemic limb blood perfusion ratios, higher capillary densities, and improved EPC mobilization.

Conclusion: Chronic hyperglycemia impaired blood flow recovery and EPC mobilization in response to tissue ischemia, and pretreatment of melatonin could reduce these effects.


C. Kuo: None. P. Huang: None. S. Lin: None.

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