Abstract
Vascular endothelial growth factor (VEGF) and platelet-derived lipid sphingosine-1-phosphate (S1P) are two proinflammatory mediators which contribute to angiogenesis, in part through the synthesis of platelet-activating factor (PAF). The red grape skin polyphenolic extract (SGE) both prevents and inhibits angiogenesis in the Matrigel model, decreases the basal motility of endothelial and cancer cells, and reverses the chemotactic effect of S1P and VEGF on bovine aortic endothelial cells (BAECs) as well as the chemotactic effect of conditioned medium on human HT-1080 fibrosarcoma, human U-87 glioblastoma, and human DAOY medulloblastoma cells. Inhibition of VEGF- and S1P-mediated chemotaxis by SGE is associated with a down-regulation of ERK and p38/MAPK phosphorylation and a decreased in acute PAF synthesis. Notably, as do extracellular inhibitors of PAF receptor, SGE prevents S1P-induced PAF synthesis and the resulting activation of the S1P/endothelial differentiation gene-1 cascade. Given the key role of VEGF and S1P in inflammation, angiogenesis, and tumor invasion, SGE may therefore contribute to prevent (or to delay) the development of diseases associated with angiogenesis dysregulation, including cancer. The dual inhibition of S1P- and VEGF-mediated migration of endothelial cell and of serum-stimulated migration of U-87 cells suggests a usefulness of SGE against highly invasive human glioblastoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aorta / cytology
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Aorta / drug effects
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Aorta / metabolism
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Cattle
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Cell Movement / drug effects
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Cells, Cultured
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Chemotaxis*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects*
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Endothelium, Vascular / metabolism
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Fibrosarcoma / drug therapy
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Fibrosarcoma / metabolism
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Fibrosarcoma / pathology
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Flavonoids / therapeutic use*
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Glioblastoma / drug therapy
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Glioblastoma / metabolism
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Glioblastoma / pathology
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Humans
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Lysophospholipids / pharmacology*
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Medulloblastoma / drug therapy
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Medulloblastoma / metabolism
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Medulloblastoma / pathology
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Neovascularization, Pathologic
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Neovascularization, Physiologic
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Phenols / therapeutic use*
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Phosphorylation / drug effects
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Platelet Activating Factor / antagonists & inhibitors
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Platelet Activating Factor / metabolism*
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Platelet Membrane Glycoproteins / antagonists & inhibitors
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Platelet Membrane Glycoproteins / metabolism
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Polyphenols
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Receptors, G-Protein-Coupled / metabolism
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Sphingosine / analogs & derivatives*
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Sphingosine / pharmacology
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Vascular Endothelial Growth Factor A / pharmacology*
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Vitis*
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Flavonoids
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Lysophospholipids
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Phenols
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Platelet Activating Factor
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Platelet Membrane Glycoproteins
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Polyphenols
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Receptors, G-Protein-Coupled
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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platelet activating factor receptor
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sphingosine 1-phosphate
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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Sphingosine