My laboratory recently uncovered an unexpected and intriguing role for a lymphatic vessels during skin wound healing. In particular, we identified that mice without lymphatic vessels display hypervascular regeneration and fibrosis after injury. Our findings are important for several reasons. First, while lymphatic vessels have been shown to be important for skin repair, the precise function of these cells in skin repair is poorly understood. Second, our data reveal that unknown mechanisms involving lymphatic vessels control blood vessel repair and skin fibrosis, two conditions that impact wound healing and excessive scarring. Finally, lymphedema, a chronic, debilitating and incurable swelling that can be a result of damage to the lymphatic vessel system due to surgery, cancer, treatments, or injury, affects over 10 million Americans. Through these focused and complementary Specific Aims, the work proposed in this application will take advantage of multiple genetic mouse models that allow specific depletion of lymphatic vessels, state of the art genomics, cell culture models. We will (1) identify the cellular and molecular mechanisms that drive lymphatic endothelial regeneration in the skin, (2) analyze the function of lymphatic endothelium cells in suppressing blood vessel repair and contributing to fibrosis, and (3) define whether enhancing lymphatic vessel repair ameliorates defective wounds of aged and diabetic mice. These studies will identify specific pro-healing cells and molecular mechanisms that can be utilized to promote healing in human patients with defective wound healing or lymphatic disorders.