Compromised angiogenesis and vascular Integrity in impaired diabetic wound healing

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, Sema-phorin3a, 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.

Macrophage Dysregulation and Impaired Skin Wound Healing in Diabetes

“…Dysregulated Mϕ activity in diabetic wounds impairs processes critical for normal wound healing. For example, Mϕ are known to play important roles in neovascularization during wound healing, and decreased production of VEGF-A as well as reduced VEGFR1 signaling by diabetic wound Mϕ likely contribute to impaired angiogenesis in diabetic wounds ( Stockmann et al, 2011 ; Willenborg et al, 2012 ; Okizaki et al, 2016 ; Okonkwo and DiPietro, 2017 ; Gurevich et al, 2018 ; Okonkwo et al, 2020 ). Mϕ likely also play important roles in the impaired maturation and remodeling of the vasculature in diabetic wounds.…”

Recombinant Myxoma Virus-Derived Immune Modulator M-T7 Accelerates Cutaneous Wound Healing and Improves Tissue Remodeling

“…Angiogenesis is a critical component of wound healing, and several comorbidities associated with impaired wound healing, such as diabetes, also exhibit reduced angiogenesis [ 57 , 58 ]. Angiogenesis plays a critical role in providing the sufficient delivery of blood and nutrients, and access to reparative immune cells, during the course of healing.…”

Catecholamines in the regulation of angiogenesis in cutaneous wound healing

“…These processes, in turn, disrupt tissue regeneration and restoration of a functional vascular system, which leads to delayed wound closure. 39,43 The angiopoietin 1/angiopoietin 2/TEK tyrosine kinase (Ang1/Ang2/Tie2) pathway also plays a role in the defective angiogenic process seen in diabetic F I G U R E 1 Schematic diagram showing that angiogenesis is an important step during the proliferative phase of dermal wound healing (Created with BioRender.com). FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; TGFβ, transforming growth factor beta; VEGF-A, vascular endothelial growth factor-A wounds.…”

“…Diabetic wound healing and angiogenesis present a global challenge clinically as well as in research settings. As evident in both clinical and experimental diabetes, the disease affects all stages of wound healing, resulting in an impaired healing capacity 39,42,43 . Disruptions in hemostasis and inflammation, matrix deposition, and angiogenesis in the wound bed are associated with nonhealing cutaneous diabetic wounds.…”

“…During normal wound healing, angiogenesis depends upon an intricate balance between pro‐ and antiangiogenic factors, which maintains the balance between vessel growth promotion, vessel maturation, and quiescence 4,8,10 . However, the scenario changes during diabetes, where a decrease in the pro‐angiogenic stimulus is noted 39,42 . In diabetes, macrophages, one of the major sources of VEGF‐A and other pro‐angiogenic mediators, as well as fibroblasts undergo phenotypic changes and have altered functions 44 .…”