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

Tae Wook Chung, Seok Jo Kim, Hee Jung Choi, Keuk Jun Kim, Mi Jin Kim, Sung Hoon Kim, Hyo Jeong Lee, Jeong Heon Ko, Young Choon Lee, Akemi Suzuki, Cheorl Ho Kim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)229-239
Number of pages11
JournalGlycobiology
Volume19
Issue number3
DOIs
StatePublished - 2009

Keywords

  • Angiogenesis
  • Ganglioside GM3
  • Vascular endothelial growth factor (VEGF)
  • Vascular endothelial growth factor receptor-2 (VEGFR-2)

ASJC Scopus subject areas

  • Biochemistry

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