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J. Biol. Chem., Vol. 280, Issue 38, 32792-32800, September 23, 2005

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A Synthetic Glycosaminoglycan Mimetic Binds Vascular Endothelial Growth Factor and Modulates Angiogenesis^*

Vincent Rouet1, Yamina Hamma-Kourbali, Emmanuel Petit, Panagiota Panagopoulou¶, Panagiotis Katsoris¶, Denis Barritault¶, Jean-Pierre Caruelle, and José Courty2

From the Laboratoire de Recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires UMR CNRS 7149, Université Paris XII-Val de Marne, Avenue du Général de Gaulle, 94010 Créteil CEDEX, France, the Organes Tissus Régénération Réparation Remplacement (OTR3), SAS, 4 rue Française, 75001 Paris, and the ^¶Division of Genetics, Cell & Development Biology, Department of Biology, University of Patras, GR 26504 Patras, Greece

In a previous study, we showed that in situ injection of glycosaminoglycan mimetics called RGTAs® (ReGeneraTing Agents) enhanced neovascularization after skeletal muscular ischemia (Desgranges, P., Barbaud, C., Caruelle, J. P., Barritault, D., and Gautron, J. (1999) FASEB J. 13, 761–766). In the present study, we showed that the RGTA® OTR4120 modulated angiogenesis in the chicken embryo chorioallantoic membrane assay, in a dose-dependent manner. We therefore investigated the effect of OTR4120 on one of the most specific angiogenesis-regulating heparin-binding growth factors, vascular endothelial growth factor 165 (VEGF₁₆₅). OTR4120 showed high affinity binding to VEGF₁₆₅ (K_d = 2.2 nM), as compared with heparin (K_d = 15 nM), and potentiated the affinity of VEGF₁₆₅ for VEGF receptor-1 and -2 and for neuropilin-1. In vitro, OTR4120 potentiated VEGF₁₆₅-induced proliferation and migration of human umbilical vein endothelial cells. In the in vivo Matrigel^TM plug angiogenesis assay, OTR4120 in a concentration as low as 3 ng/ml caused a 6-fold increase in VEGF₁₆₅-induced angiogenesis. Immunohistochemical staining showed a larger number of well differentiated VEGFR-2-expressing-cells in Matrigel^TM sections of OTR4120-treated plug than in control sections. These findings indicate that OTR4120 enhances the VEGF₁₆₅-induced angiogenesis and therefore may hold promise for treating disorders characterized by deficient angiogenesis.

Received for publication, April 25, 2005 , and in revised form, July 8, 2005.

^* This work was supported in part by Grant 4248 from the Association pour la Recherche sur le Cancer and by grants from the Ministère de l'Education Nationale (DRED) and CNRS. 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 Received a grant from the Ministère de la Recherche et de l'Enseignement Supérieur and is currently employed by Université Paris XII-Val de Marne.

² To whom correspondance should be addressed: Laboratoire de Recherche sur la Croissance Cellulaire, la Réparation et la Régénération Tissulaires UMR CNRS 7149, Université Paris XII Val de Marne, Ave. du Général de Gaulle, 94010 Créteil CEDEX, France. Tel.: 33-1-45-17-17-97; Fax: 33-1-45-17-18-16; E-mail: courty{at}univ-paris12.fr.

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