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Glycobiology Advance Access published online on October 20, 2004
Glycobiology, doi:10.1093/glycob/cwi007
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Received May 28, 2004
Revised September 14, 2004
Accepted October 14, 2004

COMMUNICATIONS

Undersulfated, low molecular weight glycol-split heparin as an antiangiogenic VEGF antagonist

Claudio Pisano 1, Concetta Aulicino 1, Loredana Vesci 1, Benito Casu 2, Annamaria Naggi 2, Giangiacomo Torri 2, Domenico Ribatti 3, Mirella Belleri 4, Marco Rusnati 4, and Marco Presta 4*

1 Sigma-Tau Research Department, 0040 Pomezia, Rome, Italy
2 G. Ronzoni Institute for Chemical and Biochemical Research, 20133 Milan, Italy
3 Department of Human Anatomy and Histology, University of Bari, 70124 Bari, Italy
4 Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, University of Brescia, 25123 Brescia, Italy

* To whom correspondence should be addressed.
Marco Presta, E-mail: presta{at}med.unibs.it


  Abstract

Vascular endothelial growth factor (VEGF) represents a target for antiangiogenic therapies in a wide spectrum of diseases, including cancer. As a novel strategy to generate non-anticoagulant antiangiogenic substances exploiting binding to VEGF while preventing receptor engagement, we assessed the VEGF-antagonist activity of a low molecular weight (LMW) compound (ST2184, Mw = 5,800) generated by depolymerization of an under-sulfated glycol-split heparin derivative. The parental compound was obtained by introducing regular sulfation gaps along the prevalently N-sulfated heparin regions, followed by glycol-splitting of all nonsulfated uronic acid residues (approximately 50% of total uronic acid residues). ST2184 was endowed with a negligible anticoagulant activity after s.c. injection in mice. ST2184 binds VEGF165 as evaluated by its capacity to retard 125I-VEGF165 electrophoretic migration in a gel mobility shift assay and to prevent VEGF165 interaction with heparin immobilized onto a BIAcore sensor chip. Unlike heparin, ST2184 was unable to present 125I-VEGF165 to its high affinity receptors in endothelial cells and inhibited VEGF165-induced neovascularization in the chick embryo chorioallantoic membrane. Undersulfated, LMW glycol-split heparins may therefore provide the basis for the design of novel non-anticoagulant angiostatic compounds.

Keywords: angiogenesis; heparin; VEGF; endothelium; growth factor receptor.
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