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J. Biol. Chem., Vol. 281, Issue 44, 33597-33605, November 3, 2006

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Neprilysin Inhibits Angiogenesis via Proteolysis of Fibroblast Growth Factor-2^*

Oscar B. Goodman, Jr.¹, Maria Febbraio^¶, Ronit Simantov^||, Rong Zheng, Ruoqian Shen, Roy L. Silverstein^¶, and David M. Nanus²

From the Urologic Oncology Research Laboratory, Department of Urology and the Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University-New York Presbyterian Hospital, New York, New York 10021, ^¶Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, and ^||Bayer Pharmaceuticals, Inc., West Haven, Connecticut 06516-4175

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

Received for publication, March 16, 2006 , and in revised form, August 14, 2006.

^* This work was supported in part by National Institutes of Health Grant CA80240, DOD Grant PC040758, and the Robert H. McCooey Memorial Cancer Research Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a fellowship from the Sass Foundation for Medical Research and an American Society of Clinical Oncology Young Investigator Award.

² To whom correspondence should be addressed: Weill Medical College of Cornell University, 525 E. 68th St., ST-359, New York, NY 10021. Tel.: 212-746-3152; Fax: 212-746-6645; E-mail: dnanus{at}med.cornell.edu.

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