Introduction: Delayed wound healing is a tremendous financial burden on healthcare, and a devastating personal burden for patients facing infections, decreased quality of life, and amputations. Dysfunctional lymphatics have been observed in delayed wound healing: in diabetes, metabolic syndrome, and lymphedema. Vascular endothelial growth factor receptor 3 (VEGFR3) is important for adult lymphangiogenesis. The effect of dysfunctional lymphangiogenesis on angiogenesis in wound healing is unknown.
Methods: We used an excisional wound model of punch biopsies to create full thickness wounds on the dorsal skin of mice. We evaluated wound healing in a mouse model with no peripheral lymph nodes and decreased lymphatics due to knockout of lymphotoxin-a (LTa KO). Additionally, inducible conditional knock-out mouse models allowed us to evaluate healing when there is decreased expression of VEGFR3 in lymphatic endothelial cells, under the control of a Cdh5CreERT2 recombinase and a Prox1CreERT2 recombinase (VEGFR3 cKO). Immunohistochemistry revealed changes in tissue architecture with identification of variations in cell populations, the latter confirmed by flow cytometry. We also isolated endothelial cells from wound beds and characterized changes in gene expression.
Results: LTa KO and VEGFR3 cKO mice displayed a decrease in lymphatic networks in uninjured and injured skin. Wound beds of VEGFR3 cKO mice exhibited increased hyperemia and angiogenesis. There was decreased apoptosis of blood endothelial cells in VEGFR3 cKO mice. Re-epithelialization of the wounds in VEGFR3 cKO mice, and migration of fibroblasts and immune cells were similar to littermate controls. However, wound beds of VEGFR3 cKO mice also have longterm changes, including defects in dermal remodeling.
Conclusions: Increased angiogenesis in mice lacking proper lymphangiogenesis during skin repair highlights the intertwined nature of these vascular systems. One contributing mechanism was decreased apoptosis of blood endothelial cells in the wound bed. There may also be a role for increased chemotaxis as part of this hyperangiogenesis phenotype. Future work will explore how these types of endothelial cells interact during dermal wound healing and how lymphatics influence dermal remodeling mechanisms.
|School Location:||United States -- Connecticut|
|Source:||DAI-B 80/07(E), Dissertation Abstracts International|
|Keywords:||Lymphatics, Skin, Vasculature, Wounds|
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