Compromised Angiogenesis, Increased Vessel Permeability, And Decreased Pericyte Coverage In Impaired Diabetic Skin Wounds
Uzoagu A. Okonkwo1, Lin Chen1, Da Ma2, Veronica A. Haywood1, May Barakat1, Norifumi Urao1, Luisa A. DiPietro1.
1University of Illinois at Chicago, Chicago, IL, USA, 2Guanghua School of Stomatology, SunYat-sen University, Guangzhou, China.
Vascular deficits are recognized as a fundamental contributing factor of diabetes-associated diseases. Although previous studies have demonstrated that the pro-angiogenic phase of wound healing is largely 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 confirmed that diabetic db/db mice demonstrated significantly slower rates of closure and impaired angiogenesis during wound healing when compared to wild type mice. MicroCT analysis of the 3-dimensional architecture of the capillary bed showed that 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 capillary pericyte coverage. We further examined the expression of a large group of known factors that influence capillary recruitment, maturation, and stability, along with markers that are expressed in dermal pericytes. Diabetic wounds had significant perturbations in factors that affect vascular regrowth, maturation and stability. Specifically, VEGF-A, SPRY2, PEDF, LRP6, TSP1, CXCL10, CXCR3, PDGFR-β, HB-EGF, EGFR, TGFβ-1, Sema3a, NRP1, Ang2, NG2, and RGS5 expression was down-regulated in diabetic wounds when compared to WT wounds. These findings were congruent with existing genomic data from human diabetic foot ulcers (GEO- GSE80178). Together, these studies provide novel information about the complex perturbations that occur during angiogenesis and vessel maturation in diabetic wounds. Therapeutic approaches that target factors responsible for vessel regression, maturation, and pruning, as well those that affect pericyte recruitment, maturation, and stability may have the potential to improve diabetic skin wound healing.
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