**3. Effects of Low Levels of VEGF**

The experiments carried out by Oosthuyse et al. in 2001 [5] were the first to suggest that VEGF acted as a neurotrophic factor at the CNS, as the reduction of VEGF function induced a specific degeneration of motoneurons in the adult mice. In these experiments, manipulation of the VEGF gene resulted in homozygous knock-in mice (VEGFδ/δ), in which the sequence of the hypoxia response element in the VEGF promoter region was removed. Consequently, these mice lost the ability to increase VEGF expression in a hypoxic situation. This alteration caused them severe muscle weakness due to the degeneration of the lower motoneurons, and they became progressively less mobile, with symptoms reminiscent of neuropathological signs of ALS. Although basal VEGF levels in muscles, heart, and fibroblasts were unaffected by removing the hypoxia response element, an overall 40% reduction of the neurotrophic factor was observed in neural tissue.

Those results obtained with the VEGFδ/<sup>δ</sup> mice allowed linking for the first time a low level of VEGF with motoneuronal degeneration. Besides, mice resulting from the crossing of the SOD1 mutant with VEGFδ/<sup>δ</sup> mice exhibited an even more drastic reduction in VEGF levels, thence a more severe degeneration of motoneurons and an earlier onset of symptoms of muscle weakness [17]. All these findings granted VEGF an unexpected neuroprotective role in the degenerative processes that accompany the pathogenesis of motoneurons, supporting the idea that motoneurons seem to be particularly sensitive to a low VEGF support [5,34,71]. Thus, a link was established between low levels of VEGF and neurodegeneration of motoneurons, such as occurs in ALS, and raised great expectation in VEGF as a possible candidate for ALS specific treatment.
