Vascular endothelial growth factor: an essential neurotrophic factor for motoneurons?

Vascular endothelial growth factor (VEGF), an angiogenic factor with neuroprotective effects: The VEGF was initially characterized by its vasculogenic and angiogenic activities and its capacity to promote vascular permeability (Yancopoulos et al., 2000). VEGF is also known as VEGF-A and is the prototype member of a related group of five trophic factors, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PlGF; Lange et al., 2016). Interestingly, VEGF-B shares a high degree of homology with VEGF but, in contrast to VEGF, has low angiogenic activity and is not pro-inflammatory. VEGF-A binds to two tyrosine quinase receptors, named VEGFR-1 and VEGFR-2, and also to the coreceptor neuropilin-1. By contrast, VEGF-B only binds to the tyrosine kinase receptor VEGFR-1 and also to the coreceptor neuropilin-1 (Lange et al., 2016). Nowadays, it is emerging that, in addition to its vascular actions, VEGF also has a significant impact on neurons by protecting them from trauma or disease. Thus, the administration of VEGF, both in vitro and in vivo through different delivery procedures, prevents or delays the death of neurons exposed to different types of insult (Lange et al., 2016). Since the knockout mice for VEGF is not viable, leading to embryonic lethality due to insufficient development of the vascular system, cardiovascular researchers designed a mutant mice with low levels of VEGF by deleting the hypoxia response element in the promoter region of the VEGF gene. Unexpectedly, these mutant mice developed an adult-onset muscle weakness accompanied by motoneuron degeneration that resembled the human disease amyotrophic lateral sclerosis (Oosthuyse et al., 2001). This work provided a novel insight to explain motoneuron degeneration in amyotrophic lateral sclerosis, since it established, for the first time, a link between low levels of VEGF and motoneuron atrophy or death. Studies of cerebrospinal fluid samples obtained from patients suffering amyotrophic lateral sclerosis, or post-mortem investigation of human spinal cord have also confirmed a correlation between low levels of VEGF and/or its receptors and amyotrophic lateral sclerosis (Sathasivam, 2008). In this line, it was expected that the administration of VEGF in animal models of motoneuron degeneration might lead to neuroprotective effects. Several experiments indeed confirmed this possibility. When mice that overexpress VEGF (VEGF) were crossed with the mutant mice G93A superoxide dismutase 1 (SOD1), a classical model of amyotrophic lateral sclerosis, the double-transgenic mice showed delayed motoneuron loss and prolonged survival as compared to the SOD1 single-transgenic mice. Similar results were obtained when VEGF was injected intrathecally using an adeno-associated virus vector (Wang et al., 2016). Moreover, VEGF delivery with retrogradely transported lentivector to SOD1 mice also delayed the onset of the disease, slowed the progression of motoneuronal degeneration and increased life expectancy (Azzouz et al., 2004). Using a different model of motoneuron degeneration, it has also been shown that the chronic administration of VEGF in the spinal cord through a miniosmotic pump prevents the paralysis and motoneuronal death in rats exposed to excitotoxic motoneuron damage (Tovar-y-Romo et al., 2007). It is important to emphasize that VEGF can also exert neuroprotective roles in other neuronal types following different types of insult, such as ischemia, seizures, or neurological diseases (Lange et al., 2016).