Compromised angiogenesis and vascular Integrity in impaired diabetic wound healing

Uzoagu A Okonkwo,Luisa A Dipietro,Da Ma,Norifumi Urao,May Barakat,Lin Chen,Veronica A Haywood,Rudolf Kirchmair

doi:10.1371/journal.pone.0231962

Uzoagu A Okonkwo, Luisa A Dipietro + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0231962

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Abstract

Vascular deficits are a fundamental contributing factor of diabetes-associated diseases. Although previous studies have demonstrated that the pro-angiogenic phase of wound healing is blunted in diabetes, a comprehensive understanding of the mechanisms that regulate skin revascularization and capillary stabilization in diabetic wounds is lacking. Using a mouse model of diabetic wound healing, we performed microCT analysis of the 3-dimensional architecture of the capillary bed. As compared to wild type, vessel surface area, branch junction number, total vessel length, and total branch number were significantly decreased in wounds of diabetic mice as compared to WT mice. Diabetic mouse wounds also had significantly increased capillary permeability and decreased pericyte coverage of capillaries. Diabetic wounds exhibited significant perturbations in the expression of factors that affect vascular regrowth, maturation and stability. Specifically, the expression of VEGF-A, Sprouty2, PEDF, LRP6, Thrombospondin 1, CXCL10, CXCR3, PDGFR-β, HB-EGF, EGFR, TGF-β1, Semaphorin3a, Neuropilin 1, angiopoietin 2, NG2, and RGS5 were down-regulated in diabetic wounds. Together, these studies provide novel information about the complexity of the perturbation of angiogenesis in diabetic wounds. Targeting factors responsible for wound resolution and vascular pruning, as well those that affect pericyte recruitment, maturation, and stability may have the potential to improve diabetic skin wound healing.

Highlights

The increased incidence of Diabetes mellitus type 2 (DM2) is a global epidemic that affects both under-developed and developed countries including the United States
This process is mediated by pro-angiogenic modulators, primarily vascular endothelial growth factor (VEGF) [8]
Angiogenesis in diabetic wounds removed with Nair depilatory cream (Church & Dwight, Ewing, NJ, USA) which was removed with gauze moistened with sterile deionized water

Summary

Introduction

The increased incidence of Diabetes mellitus type 2 (DM2) is a global epidemic that affects both under-developed and developed countries including the United States. The complication of diabetic foot ulcers (DFUs) leads 14–24% of affected patients to require lower extremity amputation, a high-risk and life-altering procedure with a five-year mortality rate approaching 50–59% [1,2,3,4,5,6]. In the proliferative stage of wound healing, angiogenesis involves the growth of blood vessels that are characterized by their immaturity, permeability, and redundancy [7] This process is mediated by pro-angiogenic modulators, primarily vascular endothelial growth factor (VEGF) [8]. Studies on vascular function in diabetic wound healing have, for the most part, focused on the impaired angiogenic phase that occurs in diabetic wounds [14]. Wounds of diabetic mice exhibited significantly decreased expression of pro-angiogenic factors and factors responsible for pericyte recruitment and vessel maturation

Materials and methods

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