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Low Molecular Weight Fucoidan and Heparin Enhance the Basic Fibroblast Growth Factor-Induced Tube Formation of Endothelial Cells through Heparan Sulfate-Dependent 6 Overexpression

Institut National de la Santé et de la Recherche Médicale U428 (D.C., A.-M.F., B.L.B., D.H.) and Laboratoire de Génétique Moléculaire-Unité Propre de Recherche et de l'Enseignement Supérieur, Equipe d'Accueil 3618 (I.L.), Université Paris V, Paris, France; Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris, Paris, France (A.-M.F., D.H.); and Institut Française de Recherche pour l'Exploitation de la Mer, Nantes, France (S.C.-J., S.M.);

Basic fibroblast growth factor (FGF-2) activates its high-affinity receptors (FGFRs) but also acts through interaction with heparan sulfate proteoglycans (HSPG). Exogenous polysaccharides also modulate the angiogenic activity of FGF-2. We investigated the effect and mechanism of action of a low molecular weight fucoidan derivative (LMWF) on tube formation by human endothelial cells. LMWF has a better arterial antithrombotic potential in animals than low molecular weight heparin (LMWH). After stimulation of human umbilical vein endothelial cells (HUVEC) by FGF-2 and LMWF (or LMWH), we observed 1) using flow cytometry, an increase in the amount of the 6 integrin subunit; 2) using quantitative reverse transcription-polymerase chain reaction, an increase in 6 mRNA (higher with LMWF than with LMWH); and 3) using a Matrigel model, an increase in vascular tube formation (also higher with LMWF than with LMWH). A direct link between 6 overexpression and vascular tube formation was confirmed by use of an anti-6 antibody: in its presence, there was no capillary network formation on Matrigel. Unexpectedly, an anti-FGFR blocking antibody had no effect on 6 over-expression, whereas stripping off the heparan sulfate with heparitinases abolished overexpression. Overall, our data suggest that FGF-2 stimulates 6 over-expression in HUVEC, through HSPG but independently from FGFR, and that LMWF (or LMWH) modulates this interaction. Expression of heparan sulfate proteoglycan increases after ischemic injury. Given its antithrombotic properties and its ability to potentiate tube formation of endothelial cells, LMWF may have to be considered for revascularization of ischemic areas.

Address correspondence to: Dominique Helley, INSERM U428, Faculté des Sciences Pharmaceutiques et Biologiques Université Paris V, 4 avenue de l'Observatoire, 75270 Paris Cedex 06. E-mail: helley{at}pharmacie.univ-paris5.fr

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