Expression of vascular endothelial growth factor and its receptors in the central nervous system in amyotrophic lateral sclerosis

Vascular endothelial growth factor (VEGF) prolongs survival in the mutant SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS), whereas dysregulation of VEGF through deletion of its hypoxia-regulatory element causes motor neuron degeneration in mice. We investigated the expression of VEGF and its major agonist receptors in the normal central nervous system and in patients with ALS. Immunohistochemistry demonstrated similar expression patterns of VEGF and VEGF receptor 2 (VEGFR2) in the spinal cord with finely punctate staining of the neuropil and strong expression in anterior horn cells (AHCs). Granular staining on the surface of some AHCs, similar to that seen with synaptic markers, suggested synaptic labeling. VEGFR2 staining was reduced in the neuropil of ALS cases (p = 0.018) associated with a reduction of synaptophysin but not SNAP25 expression. A greater proportion of AHCs in ALS cases showed low expression of VEGF (p = 0.006) and VEGFR2 (p = 0.009) compared with controls. Expression of VEGF and VEGFR2 was confirmed by Western blotting and quantitative reverse transcriptase-polymerase chain reaction (QPCR). The similar expression patterns of VEGF and VEGFR2 suggests autocrine/paracrine effects on spinal motor neurons, and the reduction in their expression seen in ALS cases would support the hypothesis that, as in mouse models of the disease, reduced VEGF signaling may play a role in the pathogenesis of ALS.