Targeting vascular transient receptor potential vanilloid 4 activity prevents lung transplant ischemia-reperfusion...

Ischemia-reperfusion injury (IRI) and acute cellular rejection (ACR) are common postoperative complications that lead to poor outcomes in lung transplant recipients. Transient receptor potential vanilloid 4 (TRPV4) is a plasma membrane Ca²⁺ channel that controls vascular tone and integrity. We examined whether TRPV4 influences IRI and alloimmune responses in a mouse model of orthotopic lung transplantation. Recipients receiving syngeneic lungs briefly treated with a TRPV4-specific inhibitor or engrafted with syngeneic lungs with an endothelial cell-specific TRPV4 gene ablation (TRPV4^ΔEC) had better graft function, reduced endothelial cell adhesion molecule expression, and lower inflammatory cytokine expression and neutrophil recruitment. TRPV4^ΔEC lungs transplanted into immunosuppressed, major histocompatibility complex-mismatched recipients had more intragraft CD25⁺ Foxp3⁺ CD4⁺ T cells and fewer IFN-γ⁺ CD8⁺ T cells and were more resistant to IRI-induced ACR than wildtype allografts. Finally, pharmacologic inhibition of TRPV4 reduced donor antigen-triggered production of IFN-γ and IL-17A by intragraft T cells and prevented ACR despite IRI. Our findings show that pulmonary endothelial cell TRPV4 activity couples ischemic tissue injury to T cell alloimmunity, highlighting the potential of therapies that enhance vascular integrity to promote transplant tolerance.