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J. Biol. Chem., Vol. 280, Issue 36, 31508-31515, September 9, 2005

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Heparin Regulates Vascular Endothelial Growth Factor₁₆₅-dependent Mitogenic Activity, Tube Formation, and Its Receptor Phosphorylation of Human Endothelial Cells

COMPARISON OF THE EFFECTS OF HEPARIN AND MODIFIED HEPARINS^*

Satoko Ashikari-Hada, Hiroko Habuchi, Yutaka Kariya, and Koji Kimata¶

From the Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195 and Central Research Laboratories, Seikagaku Corporation, Tateno, Higashiyamato-shi, Tokyo 207-0021, Japan

Vascular endothelial growth factor (VEGF) is a family of glycoproteins with potent angiogenic activity. We reported previously that heparin has an affinity for VEGF₁₆₅, the major isoform of VEGF, whereas 2-O-desulfated heparin and 6-O-desulfated heparin have weak but significant affinity (Ashikari-Hada, S., Habuchi, H., Kariya, Y., Itoh, N., Reddi, A. H., and Kimata, K. (2004) J. Biol. Chem. 279, 12346–12354). In this study, we first examined the effect of heparin and modified heparins (completely desulfated N-sulfated heparin, 2-O-desulfated heparin, and 6-O-desulfated 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 hexuronic acid and the 6-O-sulfation group of N-sulfoglucosamine in heparin/heparan sulfate 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 trisulfated disaccharide units of cell surface HS by sodium chlorate treatment resulted in the reduction of such phosphorylation, suggesting the involvement of a 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 a heparin-like domain of heparan sulfate/heparin forms a complex with VEGF₁₆₅ and VEGFR-2 via the exon 7-encoded region, thereby enhancing VEGF₁₆₅-dependent signaling.

Received for publication, December 27, 2004 , and in revised form, July 1, 2005.

^* This work was supported in part by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science; Grant-in-aid 14082206 for scientific research on priority areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and by a special research fund from the Seikagaku Corporation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Institute for Molecular Science of Medicine, Aichi Medical University, 21 Karimata, Yazako, Nagakute, Aichi 480-1195, Japan. Tel.: 81-52-264-4811 (ext. 2088); Fax: 81-561-63-3532; E-mail: kimata{at}aichi-med-u.ac.jp.

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