Junctional adhesion molecule A orchestrates endothelial cell-driven angiogenesis and wound healing in diabetes

Diabetic wounds are characterized by impaired angiogenic response and poor vascular networks. Therefore, exploring the underlying mechanism and thus developing the therapeutic strategy targeting angiogenesis hold great promise in diabetic wound healing. JAM-A, a classical cell adhesion molecule, is implicated to participate multifunctional biological processes in diverse cells; however, the precise involvement of endothelial cells (ECs) JAM-A in diabetic wound healing remains unknown. Here, we found that JAM-A predominance in cutaneous endothelia was significantly reversed in diabetic environment and JAM-A restoration in ECs orchestrated angiogenic capacities and alleviated inflammatory response which were deteriorated by sustained hyperglycemic culture. An ECs-specific gene therapy based on lipid nanoparticles was further designed and resulted in ECs JAM-A restoration with significantly better angiogenesis, improved inflammatory microenvironment and accelerated wound healing in diabetes. This therapeutic effect was mainly mediated by the activation of PI3K/AKT/mTOR signaling pathway. Our data reveal that ECs JAM-A may represent a new therapeutic target in diabetic wound and potentially other diseases characterized by impaired angiogenesis.