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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:71.)
© 2005 American Heart Association, Inc.

Vascular Biology

Antiangiogenic Activity of Semisynthetic Biotechnological Heparins

Low-Molecular-Weight-Sulfated Escherichia coli K5 Polysaccharide Derivatives as Fibroblast Growth Factor Antagonists

Marco Presta; Pasqua Oreste; Giorgio Zoppetti; Mirella Belleri; Elena Tanghetti; Daria Leali; Chiara Urbinati; Antonella Bugatti; Roberto Ronca; Stefania Nicoli; Emanuela Moroni; Helena Stabile; Maura Camozzi; German Andrés Hernandez; Stefania Mitola; Patrizia Dell’Era; Marco Rusnati; Domenico Ribatti

From the Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology (M.P., M.B., E.T., D.L., C.U., A.B., R.R., S.N., E.M., H.S., M.C., G.A.H, S.M., P.D., M.R.), School of Medicine, University of Brescia; Glycores 2000 Srl (P.O., G.Z.), Milano; and the Department of Human Anatomy and Histology (D.R.), University of Bari, Italy.

Correspondence to Marco Presta, General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, viale Europa 11, 25123 Brescia, Italy. E-mail presta{at}med.unibs.it

Objective— Low-molecular-weight heparin (LMWH) exerts antitumor activity in clinical trials. The K5 polysaccharide from Escherichia coli has the same structure as the heparin precursor. Chemical and enzymatic modifications of K5 polysaccharide lead to the production of biotechnological heparin-like compounds. We investigated the fibroblast growth factor-2 (FGF2) antagonist and antiangiogenic activity of a series of LMW N,O-sulfated K5 derivatives.

Methods and Results— Surface plasmon resonance analysis showed that LMW-K5 derivatives bind FGF2, thus inhibiting its interaction with heparin immobilized to a BIAcore sensor chip. Interaction of FGF2 with tyrosine-kinase receptors (FGFRs), heparan sulfate proteoglycans (HSPGs), and _vß₃ integrin is required for biological response in endothelial cells. Similar to LMWH, LMW-K5 derivatives abrogate the formation of HSPG/FGF2/FGFR ternary complexes by preventing FGF2-mediated attachment of FGFR1-overexpressing cells to HSPG-bearing cells and inhibit FGF2-mediated endothelial cell proliferation. However, LMW-K5 derivatives, but not LMWH, also inhibit FGF2/_vß₃ integrin interaction and consequent FGF2-mediated endothelial cell sprouting in vitro and angiogenesis in vivo in the chick embryo chorioallantoic membrane.

Conclusions— LMW N,O-sulfated K5 derivatives affect both HSPG/FGF2/FGFR and FGF2/_vß₃ interactions and are endowed with FGF2 antagonist and antiangiogenic activity. These compounds may provide the basis for the design of novel LMW heparin-like angiostatic compounds.

Low-molecular-weight compounds from a N,O-sulfated derivative of Escherichia coli K5 polysaccharide bind fibroblast growth factor-2, thus inhibiting its receptor interactions. They also inhibit endothelial cell proliferation and sprouting and angiogenesis in vivo. These semisynthetic biotechnological heparin-like compounds may provide the basis for the design of novel angiostatic molecules.

Key Words: angiogenesis • endothelium • FGF • heparin • integrin

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