Abstract
Vascular endothelial growth factor (VEGF) is reported to play a neuroprotective role through a VEGF receptor, fetal liver kinase-1 (Flk-1) in vitro. We investigated whether reduction of Flk-1 could induce motor neuron loss in rat spinal cord by inhibiting the expression of Flk-1 in rat spinal cord using antisense oligodeoxynucleotides (ODNs) against the Flk-1 receptor. Rat spinal cord was repetitively exposed to 12% hypoxia, and the change of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway and the mitogen-activated protein kinase kinase (MEK)/extracellular-signal-regulated kinase (ERK) pathway was examined. Intrathecal infusion of Flk-1 antisense ODNs for 7 days suppressed almost completely Flk-1 expression in the lumbar segment of the spinal cord and was followed by a hypoxic challenge with 12% oxygen for 1 h that was repeated for 7 more days. In the lumbar segment, we observed that reduced Flk-1 expression and hypoxic challenge for 7 days resulted in approximately 50% loss of motor neurons, in which the activation of Akt and ERK, that is, increased levels of phosphorylated-Akt and of phosphorylated-ERK by hypoxia, was markedly inhibited. In contrast, the reduction of Flk-1 expression alone did not induce motor neuron loss. These results suggest that VEGF exerts its protective effect on motor neurons against hypoxia-induced toxicity by the Flk-1 receptor through the PI3-K/Akt and the MEK/ERK signaling pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Survival / drug effects
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Cell Survival / physiology
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Disease Models, Animal
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression / drug effects
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Gene Expression / physiology
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Hypoxia / metabolism*
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Hypoxia / pathology
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MAP Kinase Signaling System / physiology
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Male
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Motor Neurons / drug effects*
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Motor Neurons / metabolism
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Motor Neurons / pathology
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Nerve Degeneration / metabolism*
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Nerve Degeneration / pathology
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Oligonucleotides, Antisense / pharmacology*
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Spinal Cord / drug effects*
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Spinal Cord / metabolism
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Spinal Cord / pathology
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
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Vascular Endothelial Growth Factor Receptor-2 / genetics
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Vascular Endothelial Growth Factor Receptor-2 / metabolism*
Substances
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Oligonucleotides, Antisense
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Proto-Oncogene Proteins
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-2
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Akt1 protein, rat
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases