Based on its trophic effects on neurons and vascular cells, vascular endothelial
growth factor (
VEGF) is a promising candidate for the treatment of
neurodegenerative diseases. To evaluate the therapeutic potential of
VEGF, we here examined effects of this
growth factor on the degeneration of axotomized retinal ganglion cells (RGCs), which, as CNS-derived neurons, offer themselves in an excellent way to study neuroprotection in vivo. Making use of a transgenic mouse line that constitutively expresses human
VEGF under a
neuron-specific enolase promoter, we show that (1) the
VEGF-transgenic retina overexpresses human
VEGF, (2) RGCs carry the
VEGF receptor-2, and (3) vascular networks in normal and axotomized
VEGF-transgenic (tg) retinas do not differ from control animals. After
axotomy, RGCs of
VEGF-tg mice were protected against delayed degeneration, as compared with wild-type littermates. Western blots revealed increased phosphorylated ERK-1/2 and Akt and reduced phosphorylated p38 and activated
caspase-3 levels in axotomized
VEGF-transgenic retinas. Intravitreous
injections of pharmacological ERK-1/2 (
PD98059) or Akt (
LY294002) inhibitors showed that
VEGF exerts neuroprotection by dual activation of ERK-1/2 and Akt pathways. In view that
axotomy-induced RGC death occurs slowly and considering that RGCs are CNS-derived neurons, we predict the clinical implementation of
VEGF in
neurodegenerative diseases of both brain and retina.