Hemostasis stimulates lymphangiogenesis through release and activation of VEGFC

Abstract

Hemostasis associated with tissue injury is followed by wound healing, a complex process by which damaged cellular material is removed and tissue repaired. Angiogenic responses are a central aspect of wound healing, including the growth of new lymphatic vessels by which immune cells, protein, and fluid are transported out of the wound area. The concept that hemostatic responses might be linked to wound healing responses is an old one, but demonstrating such a link in vivo and defining specific molecular mechanisms by which the 2 processes are connected has been difficult. In the present study, we demonstrate that the lymphangiogenic factors vascular endothelial growth factor C (VEGFC) and VEGFD are cleaved by thrombin and plasmin, serine proteases generated during hemostasis and wound healing. Using a new tail-wounding assay to test the relationship between clot formation and lymphangiogenesis in mice, we find that platelets accelerate lymphatic growth after injury in vivo. Genetic studies reveal that platelet enhancement of lymphatic growth after wounding is dependent on the release of VEGFC, but not VEGFD, a finding consistent with high expression of VEGFC in both platelets and avian thrombocytes. Analysis of lymphangiogenesis after fullthickness skin excision, a wound model that is not associated with significant clot formation, also revealed an essential role for VEGFC, but not VEGFD. These studies define a concrete molecular and cellular link between hemostasis and lymphangiogenesis during wound healing and reveal that VEGFC, the dominant lymphangiogenic factor during embryonic development, continues to play a dominant role in lymphatic growth in mature animals.