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

Mol Pharm. 2019 Oct 7;16(10):4241-4251. doi: 10.1021/acs.molpharmaceut.9b00586. Epub 2019 Sep 5.

Abstract

In diabetes, abnormal angiogenesis due to hyperglycemia and endothelial dysfunction impairs wound healing and results in high risks of diabetic foot ulcers and mortality. Alternative therapeutic methods were attempted to prevent 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 conditions and in diabetic mice is investigated. Based on in vitro and in vivo studies, DNIC [Fe2(μ-SCH2CH2OH)2(NO)4] (DNIC-1) with a sustainable NO-release reactivity (t1/2 = 27.4 ± 0.5 h at 25 °C and 16.8 ± 1.8 h at 37 °C) activates the NO-sGC-cGMP pathway and displays the best pro-angiogenesis activity overwhelming other NO donors and the vascular endothelial growth factor. Moreover, this pro-angiogenesis effect of DNIC-1 restores the impaired angiogenesis in the ischemic hind limb and accelerates the recovery rate of wound closure in diabetic mice. This study translates synthetic DNIC-1 into a novel therapeutic agent for the treatment of diabetes and highlights its sustainable •NO-release reactivity on the activation of angiogenesis and wound healing.

Keywords: angiogenesis; growth factors; nitric oxide; wound healing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival
  • Cells, Cultured
  • Chick Embryo
  • Chorioallantoic Membrane / drug effects
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Drug Delivery Systems*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Female
  • Hindlimb
  • Humans
  • Iron / administration & dosage*
  • Ischemia / pathology
  • Ischemia / prevention & control
  • Mice
  • Mice, Inbred BALB C
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / prevention & control*
  • Nitric Oxide / chemistry
  • Nitric Oxide / metabolism*
  • Nitrogen Oxides / administration & dosage*
  • Vascular Endothelial Growth Factor A / metabolism
  • Wound Healing / drug effects*
  • Wounds and Injuries / pathology
  • Wounds and Injuries / prevention & control*
  • Zebrafish

Substances

  • Nitrogen Oxides
  • Vascular Endothelial Growth Factor A
  • Nitric Oxide
  • dinitrosyl iron complex
  • Iron