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Papers In Press, published online ahead of print July 15, 2005
Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195
Corresponding Author: kimata{at}amugw.aichi-med-u.ac.jp
Vascular endothelial growth factor (VEGF) is a family of glycoproteins with potent angiogenic activity. We previously reported that heparin has an affinity to VEGF165, the major isoform of VEGF, while 2-O-desulfated (2ODS) heparin and 6-O-desulfated (6ODS) heparin have weak but significant affinity (Ashikari-Hada et al., J. Biol. Chem. (2004) 279, 12346-12354). In this study, we first examined the effect of heparin and modified heparins (completely desulfated N-sulfated heparin, 2ODS heparin and 6ODS heparin) on VEGF165-dependent mitogenic activity and tube formation on type I collagen gels of human umbilical vein endothelial cells. Both were enhanced by heparin, but not by modified heparins, suggesting that both the 2-O-sulfate group of HexA and the 6-O-sulfation group of GlcNSO3 in heparin/heparan sulfate (HS) are necessary for VEGF165 activity. We then examined the activation of VEGF receptor (VEGFR) to understand the mechanism. We have made several new findings; (1) heparin yielded a 1.7-fold enhancement of VEGF165-induced phosphorylation of VEGFR-2, (2) depletion of cell surface heparan sulfate by heparinase/heparitinase treatment and preferential reduction of tri-sulfated disaccharide units of cell surface HS by sodium chlorate treatment resulted in the reduction of such phosphorylation, suggesting the involvement of heparin-like domain in the phosphorylation of VEGFR-2, and (3) VEGF121, an isoform without the exon 7-encoded region, which has no capacity to bind to heparin did not show these effects. It is therefore likely that heparin-like domain of HS/heparin forms a complex with VEGF165 and VEGFR-2 via the exon 7-encoded region, thereby enhancing VEGF165-dependent signaling.
J. Biol. Chem, 10.1074/jbc.M414581200
Submitted on December 27, 2004
Accepted on July 15, 2005
Heparin regulates VEGF165-dependent mitogenic activity, tube formation and its receptor phosphorylation of human endothelial cells: Comparison of the effects of heparin and modified heparins
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