Abstract
Many diseases, including cancer, have been associated with impaired regulation of angiogenesis, of which vascular endothelial growth factor (VEGF)-A is a key regulator. Here, we test the contribution of N-myc downstream regulated gene 1 (NDRG1) to VEGF-A-induced angiogenesis in vascular endothelial cells (ECs). Ndrg1-/- mice exhibit impaired VEGF-A-induced angiogenesis in corneas. Tumor angiogenesis induced by cancer cells that express high levels of VEGF-A was also reduced in a mouse dorsal air sac assay. Furthermore, NDRG1 deficiency in ECs prevented angiogenic sprouting from the aorta and the activation of phospholipase Cγ1 (PLCγ1) and ERK1/2 by VEGF-A without affecting the expression and function of VEGFR2. Finally, we show that NDRG1 formed a complex with PLCγ1 through its phosphorylation sites, and the inhibition of PLCγ1 dramatically suppressed VEGF-A-induced angiogenesis in the mouse cornea, suggesting an essential role of NDRG1 in VEGF-A-induced angiogenesis through PLCγ1 signaling.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inducing Agents / pharmacology*
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Animals
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cells, Cultured
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Corneal Neovascularization / enzymology*
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Corneal Neovascularization / genetics
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Corneal Neovascularization / pathology
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Disease Models, Animal
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Endothelial Cells / drug effects*
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Endothelial Cells / enzymology
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Endothelial Cells / pathology
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Female
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Humans
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Male
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Mice, Inbred C57BL
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Mice, Knockout
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Neovascularization, Physiologic / drug effects*
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Phospholipase C gamma / metabolism*
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Signal Transduction
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Vascular Endothelial Growth Factor A / pharmacology*
Substances
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Angiogenesis Inducing Agents
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Cell Cycle Proteins
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Intracellular Signaling Peptides and Proteins
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N-myc downstream-regulated gene 1 protein
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Extracellular Signal-Regulated MAP Kinases
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Phospholipase C gamma
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Plcg1 protein, mouse