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J. Biol. Chem., Vol. 281, Issue 49, 37844-37852, December 8, 2006

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Low Molecular Weight Fucoidan Increases VEGF₁₆₅-induced Endothelial Cell Migration by Enhancing VEGF₁₆₅ Binding to VEGFR-2 and NRP1^*

Andrew C. Lake¹, Roger Vassy^¶, Mélanie Di Benedetto^¶, Damien Lavigne, Catherine Le Visage², Gérard Y. Perret^¶, and Didier Letourneur³

From the INSERM, U 698, Bioengineering Department, X. Bichat Hospital, 75018 Paris, the Institut Galilée, University Paris 13, 93430 Villetaneuse, and the ^¶CNRS UMR 7033, School of Medicine, University Paris 13, 93017 Bobigny, France

Therapeutic induction of angiogenesis is a potential treatment for chronic ischemia. Heparan sulfate proteoglycans are known to play an important role by their interactions with proangiogenic growth factors such as vascular endothelial growth factor (VEGF). Low molecular weight fucoidan (LMWF), a sulfated polysaccharide from brown seaweeds that mimic some biological activities of heparin, has been shown recently to promote revascularization in rat critical hindlimb ischemia. In this report, we first used cultured human endothelial cells (ECs) to investigate the possible ability of LMWF to enhance the actions of VEGF₁₆₅. Data showed that LMWF greatly enhances EC tube formation in growth factor reduced matrigel. LMWF is a strong enhancer of VEGF₁₆₅-induced EC chemotaxis, but not proliferation. In addition, LMWF has no effect on VEGF₁₂₁-induced EC migration, a VEGF isoform that does not bind to heparan sulfate proteoglycans. Then, with binding studies using ¹²⁵I-VEGF₁₆₅, we observed that LMWF enhances the binding of VEGF₁₆₅ to recombinant VEGFR-2 and Neuropilin-1 (NRP1), but not to VEGFR-1. Surface plasmon resonance analysis showed that LMWF binds with high affinity to VEGF₁₆₅ (1.2 nM) and its receptors (5-20 nM), but not to VEGF₁₂₁. Pre-injection of LMWF on immobilized receptors shows that VEGF₁₆₅ has the highest affinity for VEGFR-2 and NRP1, as compared with VEGFR-1. Overall, the effects of LMWF were much more pronounced than those of LMW heparin. These findings suggested an efficient mechanism of action of LMWF by promoting VEGF₁₆₅ binding to VEGFR-2 and NRP1 on ECs that could help in stimulating therapeutic revascularization.

Received for publication, January 24, 2006 , and in revised form, July 27, 2006.

^* This work was supported by Inserm, University Paris 7 and University Paris 13 (BQR and IFR Paris-Nord Plaine de France). 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 Recipient of a postdoctoral fellowship from University Paris 13.

² Recipient of a grant from the Young Investigator Program funded by INSERM.

³ To whom correspondence should be addressed: INSERM U 698, X. Bichat Hospital, Bât INSERM, 46 rue H. Huchard, 75018 Paris, France. Tel.: 33-1-4025-8600; Fax: 33-1-4025-8602; E-mail: letourne{at}galilee.univ-paris13.fr.

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