Molecular Mechanism of TNFSF15-Induced Inhibition of VEGF-Stimulated Vascular Hyperpermeability

Vascular hyperpermeability is critical in ischemic diseases including stroke and myocardial infarction, as well as in inflammation and cancer. VEGF-VEGFR2 signaling pathways play a central role in facilitating vascular permeability. Counter-balancing mechanisms that negatively control vascular permeability, although important to the maintenance of the integrity of blood vessels, are not yet fully understood. We report here that TNFSF15, an endothelium-derived cytokine and a specific inhibitor of vascular endothelial cell proliferation, can inhibit VEGF-induced vascular permeability in vitro and in vivo. DR3, the receptor of TNFSF15, mediates TNFSF15 induced dephosphorylation of VEGFR2 by utilizing phosphatase SHP-1, which is recruited to DR3 upon TNFSF15 interaction with the latter. A protein complex consisting of VEGFR2, DR3 and SHP-1 is formed in response to TNFSF15 and VEGF actions on endothelial cell. This protein complex plausibly provides a structural basis to the molecular mechanism in which TNFSF15 induces the inhibition of VEGF-stimulated vascular hyperpermeability.