Vascular endothelial growth factor prevents G93A-SOD1-induced motor neuron degeneration

Dev Neurobiol. 2009 Nov;69(13):871-84. doi: 10.1002/dneu.20747.


Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder characterized by selective loss of motor neurons (MNs). Twenty percent of familial ALS cases are associated with mutations in Cu(2+)/Zn(2+) superoxide dismutase (SOD1). To specifically understand the cellular mechanisms underlying mutant SOD1 toxicity, we have established an in vitro model of ALS using rat primary MN cultures transfected with an adenoviral vector encoding a mutant SOD1, G93A-SOD1. Transfected cells undergo axonal degeneration and alterations in biochemical responses characteristic of cell death such as activation of caspase-3. Vascular endothelial growth factor (VEGF) is an angiogenic and neuroprotective growth factor that can increase axonal outgrowth, block neuronal apoptosis, and promote neurogenesis. Decreased VEGF gene expression in mice results in a phenotype similar to that seen in patients with ALS, thus linking loss of VEGF to the pathogenesis of MN degeneration. Decreased neurotrophic signals prior to and during disease progression may increase MN susceptibility to mutant SOD1-induced toxicity. In this study, we demonstrate a decrease in VEGF and VEGFR2 levels in the spinal cord of G93A-SOD1 ALS mice. Furthermore, in isolated MN cultures, VEGF alleviates the effects of G93A-SOD1 toxicity and neuroprotection involves phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling. Overall, these studies validate the usefulness of VEGF as a potential therapeutic factor for the treatment of ALS and give valuable insight into the responsible signaling pathways and mechanisms involved.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology
  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Cell Death / genetics
  • Cytoprotection
  • Disease Models, Animal
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Transgenic
  • Motor Neurons / drug effects*
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Spinal Cord / cytology
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism*
  • Superoxide Dismutase / genetics*
  • Vascular Endothelial Growth Factors / metabolism
  • Vascular Endothelial Growth Factors / pharmacology*


  • Vascular Endothelial Growth Factors
  • SOD1 G93A protein
  • Superoxide Dismutase
  • Receptors, Vascular Endothelial Growth Factor