Activation of Angiogenesis and Wound Healing in Diabetic Mice Using NO-Delivery Dinitrosyl Iron Complexes.

In diabetes, abnormal angiogenesis due to the hyperglycemia and endothelial dysfunction impairs the wound healing and results in high risk of diabetic foot ulcers and mortality. The alternative therapeutic methods were attempted to prevent the diabetic complications through the activation of endothelial nitric oxide synthase. In this study, direct application of nitric oxide using dinitrosyl iron complexes (DNICs) to promote angiogenesis and wound healing under physiological condition and in diabetic mice was investigated. Based on the in vitro and in vivo studies, DNIC [Fe2(-SCH2CH2OH)2(NO)4] (DNIC-1) with a sustainable NO-release reactivity (t1/2 = 27.4 ± 0.5 h at 25 oC and 16.8 ± 1.8 h at 37 oC) activates the NO-sGC-cGMP pathway and displays the best pro-angiogenesis activity overwhelming other NO donors and vascular endothelial growth factor (VEGF). Moreover, this pro-angiogenesis effect of DNIC-1 rescues the impaired angiogenesis in ischemic hind limb and accelerates the recovery rate of wound closure in diabetic mice. This study translates the synthetic DNIC-1 into a novel chemotherapy for the treatment of diabetes and highlights its sustainable ●NO-release reactivity on the activation of angiogenesis and wound healing.