Abstract
Cultured lung endothelial cells (LEC) respond to VEGF or arachidonic acid with increases in cell proliferation, the formation of tube-like structures, and the activation of Akt and ERK1/2 mediated growth pathways. LECs express a VEGF inducible Cyp2c44 epoxygenase and its 11,12- and 14,15-EET metabolites increase cell proliferation, tubulogenic activity, and the phosphorylation states of the ERK1/2 and Akt kinases. Ketoconazole, an epoxygenase inhibitor, blocks the cellular responses to VEGF. LECs expressing a Cyp2c44 epoxygenase small interference RNA show reductions in Cyp2c44 mRNA levels, and in their VEGF-stimulated proliferative and tubulogenic capacities; effects that are associated with decreases in VEGF-induced phosphorylation of the ERK1/2 and Akt kinases. We conclude that the Cyp2c44 arachidonic acid epoxygenase is a component of the signaling pathways associated with VEGF-stimulated angiogenesis, and suggest a role for EETs in the growth factor-induced changes in the activation states of the ERK1/2 and Akt kinase pathways.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antifungal Agents / pharmacology
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Cell Proliferation / drug effects
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Cells, Cultured
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Cytochrome P-450 CYP2J2
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / metabolism*
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Cytochrome P450 Family 2
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Endothelial Cells / cytology
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Endothelial Cells / enzymology*
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Enzyme Activation / drug effects
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Ketoconazole / pharmacology
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Lung / cytology
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Lung / enzymology*
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MAP Kinase Signaling System / drug effects*
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MAP Kinase Signaling System / physiology
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Mice
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Mice, Transgenic
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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, Physiologic / drug effects*
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Neovascularization, Physiologic / physiology
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Phosphorylation / drug effects
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Phosphorylation / physiology
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor A / pharmacology*
Substances
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Antifungal Agents
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Cytochrome P-450 Enzyme Inhibitors
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RNA, Small Interfering
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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Cytochrome P-450 Enzyme System
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Cyp2c23 protein, mouse
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Cytochrome P-450 CYP2J2
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Cytochrome P450 Family 2
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Ketoconazole