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

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.

• Authors: 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
• Journal: Glycobiology (Glycobiology) Vol. 19 Issue 3 Pg. 229-39 (Mar 2009) ISSN: 1460-2423 [Electronic] England
• PMID: 18974200 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• G(M3) Ganglioside
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Angiogenesis Inhibitors (metabolism, pharmacology)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Endothelium (metabolism)
• Endothelium, Vascular (cytology)
• G(M3) Ganglioside (metabolism)
• Humans
• Neovascularization, Pathologic (metabolism)
• Umbilical Veins (cytology)
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)