Reduction of a vascular endothelial growth factor receptor, fetal liver kinase-1, by antisense oligonucleotides induces motor neuron death in rat spinal cord exposed to hypoxia.

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.

• Authors: M Shiote, I Nagano, H Ilieva, T Murakami, H Narai, Y Ohta, T Nagata, M Shoji, K Abe
• Journal: Neuroscience (Neuroscience) Vol. 132 Issue 1 Pg. 175-82 ( 2005) ISSN: 0306-4522 [Print] United States
• PMID: 15780476 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Oligonucleotides, Antisense
• Proto-Oncogene Proteins
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-2
• Akt1 protein, rat
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Cell Survival (drug effects, physiology)
• Disease Models, Animal
• Down-Regulation (drug effects, physiology)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression (drug effects, physiology)
• Hypoxia (metabolism, pathology)
• MAP Kinase Signaling System (physiology)
• Male
• Motor Neurons (drug effects, metabolism, pathology)
• Nerve Degeneration (metabolism, pathology)
• Oligonucleotides, Antisense (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects, physiology)
• Spinal Cord (drug effects, metabolism, pathology)
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, genetics, metabolism)