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Glycobiology Advance Access published online on October 30, 2008
Glycobiology, 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 Chunga, Seok-Jo Kima,e, Hee-Jung Choia, Keuk-Jun Kimb, Mi-Jin Kimb, Sung-Hoon Kimc, Hyo-Jeong Leec, Jeong-Heon Kod, Young-Choon Leee, Akemi Suzukif and Cheorl-Ho Kima,§

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

§ Corresponding author: Prof. Cheorl-Ho Kim. Molecular and Cellular Glycobiology Unit, Department of Biological Science, Sungkyunkwan University, Chunchun-Dong, Jangan-Gu, Suwon City, Kyunggi 440-746, Korea. Tel: +82-31-290-7002. Fax: +82-31-290-7015. Email: chkimbio{at}skku.edu

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

Angiogenesis is associated with growth, invasion and metastasis of human solid tumor and the aberrant activation of endothelial cells and induction of microvascular permeability by vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2)-mediated 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 signal 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 for in vivo models, such as the chick chorioallantoic membrane and matrigel plug assay. Interestingly, GM3 suppressed VEGF-induced VEGFR-2 activation by blocking VEGF receptor-2 dimerization and the binding between VEGF and VEGFR-2 through GM3-specific interaction with extracellular domain of VEGFR-2, but not VEGF. In other in vivo experiments, the growth of tumor in mice with primary tumors was obviously inhibited by subcutaneous injection of GM3. Immunohistochemical analysis showed 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 clearly inhibits VEGF/VEGFR-2-mediated vascular endothelial cell function and angiogenesis, and might be a therapeutic avenue for anti-angiogenesis.

Key words: Ganglioside GM3 / Vascular endothelial growth factor (VEGF) / Vascular endothelial growth factor receptor-2 (VEGFR-2) / Angiogenesis


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