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Angiogenesis, Metastasis, and the Cellular Microenvironment

A Fucosylated Chondroitin Sulfate From Echinoderm Modulates in Vitro Fibroblast Growth Factor 2–Dependent Angiogenesis¹

¹ INSERM U428, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, Paris, France;
² Laboratorio de Tecido Conjuntivo, Hospital Universitario and Departamento de Bioquimica Médica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

Requests for reprints: Jacqueline Tapon-Bretaudière, INSERM U428, Faculté des Sciences Pharmaceutiques, 4 avenue de l'Observatoire, 75270 Paris Cedex 06, France. Phone: (33)-1-56-09-23-32; Fax: (33)-1-56-09-33-93. E-mail: jacqueline.tapon-bretaudiere{at}hop.egp.ap-hop-paris.fr

Fucosylated chondroitin sulfate (FucCS), a glycosaminoglycan obtained from sea cucumber, has the same structure as mammalian chondroitin sulfate, but some of the glucuronic acid residues display sulfated fucose branches. This new polysaccharide has a more favorable effect than heparin on vascular cell growth. It inhibits smooth muscle cell proliferation as heparin, and it has a potent enhancing effect on endothelial cell proliferation and migration in the presence of heparin-binding growth factors. We now extend our studies to the effect of this glycosaminoglycan on endothelial cells to an in vitro angiogenesis model on Matrigel. FucCS, in the presence of fibroblast growth factor-2 (FGF-2), strongly increases the capacity of endothelial cells to form vascular tubes on Matrigel with a well-organized capillary-like network and typical closed structures. Comparison between the activity of native and chemically modified chondroitin sulfate from sea cucumber reveals that the sulfated fucose branches are the structural motif for the proangiogenic activity. Heparin does not induce angiogenesis in this experimental model. We also have evidence for the proposition that endothelial cell proliferation is not the sole event involved in the in vitro FGF-2-induced angiogenesis. It implies a variety of other modifications of the endothelial cells and of their interaction with the extracellular matrix, such as integrin expression and actin cytoskeleton reorganization. Finally, the proangiogenic effect of FucCS, concomitant with its capacity to prevent venous and arterial thrombosis, in animal models makes this new glycosaminoglycan a promising molecule with possible beneficial effects in pathological conditions affecting blood vessels such as the neovascularization of ischemic areas.

Key Words: Fucosylated chondroitin sulfate • endothelial cell • FGF-2 • angiogenesis

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