Plasminogen/thrombomodulin Signaling Enhances VEGF Expression to Promote Cutaneous Wound Healing

Plasminogen (Plg) and thrombomodulin (TM) are glycoproteins well known for fibrinolytic and anticoagulant functions, respectively. Both Plg and TM are essential for wound healing. However, their significance during the reparative process was separately demonstrated in previous studies. Here, we investigate the interaction between Plg and epithelial TM and its effect on wound healing. Characterization of the wound margin revealed that Plg and TM were simultaneously upregulated at the early stage of wound healing and the two molecules were bound together. In vitro, TM silencing or knockout in keratinocytes inhibited Plg activation. Plg treatment enhanced keratinocyte proliferation and migration, and these actions were abolished by TM antibody. Keratinocyte-expressed vascular endothelial growth factor (VEGF), which presented a dose-response relationship with Plg treatment, can be suppressed by TM silencing. Moreover, treatment with VEGF antibody inhibited Plg-enhanced keratinocyte proliferation and wound recovery. In vivo, TM antibody treatment and keratinocyte-specific TM knockout can impede Plg-enhanced wound healing in mice. In high-glucose environments, Plg-enhanced VEGF expression and wound healing were suppressed due at least in part to downregulation of keratinocyte-expressed TM. Taken together, our findings suggest that activation of Plg/TM signaling may hold therapeutic potential for chronic wounds in diabetic or non-diabetic individuals. KEY MESSAGES: Plg binds to TM in cutaneous wound healing. TM facilitates the activation of Plg to Plm in keratinocytes. Epithelial TM regulates Plg-enhanced wound healing through VEGF expression.