Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration

Hypoxia stimulates angiogenesis through the binding of hypoxia-inducible fa ctors to the hypoxia-response element in the vascular endothelial growth fa ctor (Vegf) promotor. Here, we report that deletion of the hypoxia-response element in the Vegf promotor reduced hypoxic Vegf expression in the spinal cord and caused adult-onset progressive motor neuron degeneration, reminis cent of amyotrophic lateral sclerosis, The neurodegeneration seemed to be d ue to reduced neural vascular perfusion. In addition. Vegf(165) promoted su rvival of motor neurons during hypoxia through binding to Vegf receptor 2 a nd neuropilin 1. Acute ischemia is known to cause nonselective neuronal dea th. Our results indicate that chronic vascular insufficiency and, possibly, insufficient Vegf-dependent neuroprotection lead to the select degeneratio n of motor neurons.