Abstract
VEGFR-3 is essential for vascular development and maintenance of lymphatic vessel's integrity. Little is known about its cooperative effect with other receptors of the same family. Contrary to VEGFR-2, stimulation of VEGFR-3 by VEGF-C and -D failed to enhance its phosphorylation either in HEK293T or in PAE cells. These ligands were unable to induce angiogenesis of PAEC expressing VEGFR-3 alone. In the presence of VEGFR-2, VEGF-C and -D induced heterodimerization of VEGFR-3 with VEGFR-2. This heterodimerization was associated with enhanced VEGFR-3 phosphorylation and subsequent cellular responses as evidenced by the formation of capillary-like structures in PAE cells and proliferation of primary human endothelial cells expressing both receptors. Taken together, these results show for the first time that VEGFR-3 needs to be associated to VEGFR-2 to induce ligand-dependent cellular responses.
MeSH terms
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Blotting, Western
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Carbazoles / pharmacology
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Cell Line
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Cell Proliferation
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Cells, Cultured
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Dimerization
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Endothelial Cells / cytology
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Endothelium, Vascular / cytology
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Humans
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Immunoprecipitation
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Ligands
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Neovascularization, Pathologic
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Peptides / chemistry
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Phosphorylation
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Protein Binding
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Protein-Tyrosine Kinases / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Time Factors
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Transfection
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Vascular Endothelial Growth Factor C / chemistry
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Vascular Endothelial Growth Factor D / chemistry
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Vascular Endothelial Growth Factor Receptor-2 / chemistry*
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Vascular Endothelial Growth Factor Receptor-3 / chemistry*
Substances
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3-(5,6,7,13-tetrahydro-9-((1-methylethoxy)methyl)-5-oxo-12H-indeno(2,1-a)pyrrolo(3,4-c)carbazol-12-yl)propanol
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Carbazoles
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Ligands
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Peptides
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Vascular Endothelial Growth Factor C
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Vascular Endothelial Growth Factor D
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Protein-Tyrosine Kinases
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Vascular Endothelial Growth Factor Receptor-2
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Vascular Endothelial Growth Factor Receptor-3