VEGF is a key angiogenic factor that was originally considered to be an endothelial cell-specific factor. We have shown that in knock-in mice with a subtle deletion of the hypoxia response element in the VEGF gene promoter (VEGF[delta]/[delta] mice), insufficient VEGF levels caused adult-onset motor neuron degeneration, reminiscent of the neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Furthermore, VEGF was found to be a modifier of motor neuron degeneration in SOD1 G93A mice, a mouse model of familial ALS. VEGF also has direct neurotrophic effects on motor neurons in vivo, as overexpression of Flk-1 ?a receptor for VEGF? specifically on adult neurons delays the onset of motor neuron degeneration and increases life span of SOD1 G93A mice. Vascular abnormalities also contribute to motor neuron degeneration, as cerebral blood flow (CBF) was reduced in presymptomatic VEGF[delta]/[delta]/SOD1 G93A double transgenic mice as compared to single transgenic SOD1 G93A mice. Although both angiogenesis and vascular density were normal in the nervous system, functional vascular abnormalities were found in VEGF[delta]/[delta] and VEGF[delta]/[delta]/SOD1 G93A mice. Finally, VEGF was also found to have therapeutic potential, as both intra-cerebroventricular delivery of VEGF protein to SOD1 G93A rats as viral vector mediated VEGF gene transfer to SOD1 G93A mice resulted in beneficial effects.