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Glycobiology Advance Access originally published online on October 30, 2008
Glycobiology 2009 19(3):229-239; doi:10.1093/glycob/cwn114
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© The Author 2008. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Ganglioside GM3 inhibits VEGF/VEGFR-2-mediated angiogenesis: Direct interaction of GM3 with VEGFR-2

Tae-Wook Chung2, Seok-Jo Kim2,6, Hee-Jung Choi2, Keuk-Jun Kim3, Mi-Jin Kim3, Sung-Hoon Kim4, Hyo-Jeong Lee4, Jeong-Heon Ko5, Young-Choon Lee6, Akemi Suzuki7 and Cheorl-Ho Kim1,2

2 Molecular and Cellular Glycobiology Unit, Department of Biological Science, SungKyunKwan University, 300 Chunchun-Dong, Jangan-Gu, Suwon City, Kyunggi-Do 440-746, Korea
3 Department of Pathology, College of Medicine, Yeungnam University, Daegu 705-717, Korea
4 Laboratory of Angiogenesis and Chemoprevention, College of Oriental Medicine, Kyunghee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 131-701, Korea
5 Systemic Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Yusong-Gu, Taejon 305-600, Korea
6 Faculty of Biotechnology, Dong-A University, Saha-Gu, Busan 604-714, Korea
7 Institute of Glycoscience, Tokai University, 1117 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan

1 To whom correspondence should be addressed: Tel: +82-31-290-7002; Fax: +82-31-290-7015; e-mail: chkimbio{at}skku.edu

Received on March 26, 2008; revised on October 6, 2008; accepted on October 15, 2008

Angiogenesis is associated with growth, invasion, and metastasis of human solid tumors. Aberrant activation of endothelial cells and induction of microvascular permeability by a vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) signaling pathway is observed in pathological angiogenesis including tumor, wound healing, arthritis, psoriasis, diabetic retinopathy, and others. Here, we show that GM3 regulated the activity of various downstream signaling pathways and biological events through the inhibition of VEGF-stimulated VEGFR-2 activation in vascular endothelial cells in vitro. Furthermore, GM3 strongly blocked VEGF-induced neovascularization in vivo, in models including the chick chorioallantoic membrane and Matrigel plug assay. Interestingly, GM3 suppressed VEGF-induced VEGFR-2 activation by blocking its dimerization and also blocked the binding of VEGF to VEGFR-2 through a GM3-specific interaction with the extracellular domain of VEGFR-2, but not with VEGF. Primary tumor growth in mice was inhibited by subcutaneous injection of GM3. Immunohistochemical analyses showed GM3 inhibition of angiogenesis and tumor cell proliferation. GM3 also resulted in the suppression of VEGF-stimulated microvessel permeability in mouse skin capillaries. These results suggest that GM3 inhibits VEGFR-2-mediated changes in vascular endothelial cell function and angiogenesis, and might be of value in anti-angiogenic therapy.

Key words: angiogenesis / ganglioside GM3 / vascular endothelial growth factor (VEGF) / vascular endothelial growth factor receptor-2 (VEGFR-2)


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