Neprilysin Inhibits Angiogenesis via Proteolysis of Fibroblast Growth Factor-2

摘要: Neprilysin is a cell surface peptidase that catalytically inactivates neuropeptide substrates and functions as tumor suppressor via its enzymatic function multiple protein-protein interactions. We investigated whether neutral endopeptidase could inhibit angiogenesis in vivo utilizing murine corneal pocket model found it reduced fibroblast growth factor-2-induced by 85% (p < 0.01) but had no effect on of vascular endothelial factor. Treatment with recombinant neprilysin, not enzymatically inactive resulted slight increase basic factor electrophoretic mobility from proteolytic cleavage between amino acids Leu-135 Gly-136, which was inhibited the inhibitor CGS24592 heparin. Cleavage kinetics were rapid, comparable other known neprilysin substrates. Functional studies involving neprilysin-expressing cells demonstrated inhibition significantly enhanced factor-mediated growth, capillary array formation, signaling, whereas exogenous signaling. Recombinant constructs confirmed products neither promoted formation nor induced Moreover, mutation site concomitant loss increased potency factor-2 to induce formation. These data indicate proteolytically factor-2, resulting negative regulation angiogenesis.