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J. Biol. Chem., Vol. 282, Issue 36, 26294-26305, September 7, 2007

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Semaphorin-3A and Semaphorin-3F Work Together to Repel Endothelial Cells and to Inhibit Their Survival by Induction of Apoptosis^*

From the Cancer and Vascular Biology Research Center, Rappaport Research Institute in the Medical Sciences, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, 1 Efron St., P. O. Box 9679, Haifa 31096, Israel

Semaphorin-3A (sema3A) is a neuropilin-1 (np1) agonist. It inhibits the binding of the 165-amino acid form of VEGF (VEGF₁₆₅) to np1 and was reported to inhibit angiogenesis as a result. However, we find that sema3A concentrations that inhibit the mitogenic effects of VEGF₁₆₅ do not inhibit VEGF₁₆₅-induced phosphorylation of VEGF receptor-2 (VEGFR-2). Furthermore, sema3A inhibits the biological effects of VEGF₁₂₁, a VEGF form that does not bind to neuropilins and basic fibroblast growth factor, a growth factor whose activity, unlike that of VEGF, is not inhibited by small interfering RNA directed against np1. Therefore, the mechanism by which sema3A inhibits VEGF₁₆₅ activity does not depend on competition with VEGF₁₆₅ for binding to np1. Sema3A induced rapid disappearance of focal contacts followed by collapse of the actin cytoskeleton in human umbilical vein-derived endothelial cells. HEK293 cells expressing sema3A repel human endothelial cells and at high concentrations induce their death by apoptosis. Furthermore, sema3A inhibited the formation of tubes from endothelial cells in an in vitro angiogenesis assay. Similar effects are induced by the neuropilin-2 (np2) agonist sema3F. These inhibitory effects are abrogated by small interfering RNAs directed against np1 or np2, respectively. The anti-proliferative effects of sema3A and sema3F are additive when the semaphorins are added as pure proteins. However, when sema3A and sema3F were co-expressed in HEK293 cells their pro-apoptotic and cell repellant activities appeared to be synergistic. These observations suggest that combinations of sema3A and sema3F may be able to inhibit tumor angiogenesis more effectively than single semaphorins.

Received for publication, October 16, 2006 , and in revised form, June 8, 2007.

^* This work was supported by grants from the Israel Science Foundation (ISF), Komen Breast Cancer Foundation, German-Israeli Binational Foundation (GIF), International Union against Cancer (AICR) (to G. N.), and the Rappaport Family Institute for Research in the Medical Sciences of the Faculty of Medicine at the Technion, Israel Institute of Technology (to G. N.). 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 Both authors contributed equally to the results of this article.

² To whom correspondence should be addressed. Tel.: 972-4-8295430; Fax: 972-4-8523672; E-mail: gera{at}tx.technion.ac.il.

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