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Morcuende, S. Neuroprotective effect of VEGF. Encyclopedia. Available online: (accessed on 22 June 2024).
Morcuende S. Neuroprotective effect of VEGF. Encyclopedia. Available at: Accessed June 22, 2024.
Morcuende, Sara. "Neuroprotective effect of VEGF" Encyclopedia, (accessed June 22, 2024).
Morcuende, S. (2021, February 02). Neuroprotective effect of VEGF. In Encyclopedia.
Morcuende, Sara. "Neuroprotective effect of VEGF." Encyclopedia. Web. 02 February, 2021.
Neuroprotective effect of VEGF

Vascular endothelial growth factor (VEGF) plays a crucial role as a neuroprotective factor in the nervous system. A deficit of VEGF has been related to motoneuronal degeneration, such as that occurring in amyotrophic lateral sclerosis (ALS). Strikingly, motoneurons of the oculomotor system, that show lesser vulnerability to neurodegeneration in ALS compared to other motoneurons, presente higher amounts of VEGF and its receptor Flk-1.

VEGF oculomotor system trophic factors motoneurons neurodegeneration axotomy amyo-trophic lateral sclerosis

1. Introduction

VEGF was initially described as an angiogenic factor and it was in 2001 when, his essential role in motoneuronal protection was revealed for the first time. It exerts direct trophic and neuroprotective effects on many types of neural cells, including motoneurons, astroglia, microglia, hippocampal, dopaminergic, cortical, cerebellar, sympathetic neurons, and even muscle satellite cells. It also supports synaptic plasticity and favors the growth, survival, differentiation, and migration of neuronal and glial cells. Additionally, VEGF guarantees an optimal blood and glucose supply to the brain and spinal cord, protecting motoneurons from oxidative stress, hypoxia, hypoglycemia [1], and glutamate-mediated excitotoxicity.

Several factors have been found to upregulate VEGF mRNA expression, including tumor necrosis factor (TNF-α), platelet-derived growth factor (PDGF), interleukins, angiopoietins, erythropoietins, and nitric oxide. However, the main and more robust regulator of VEGF expression is hypoxia. VEGF mRNA has a half-life of 30–45 min under normoxic conditions, whereas the mRNA half-life is prolonged in hypoxia and cells increase the production of the hypoxia-induced transcription factor 1 (HIF-1). Therefore, transactivation of HRE by the HIF-1α/HIF-1β complex stimulates the gene expression of erythropoietin, glucose transporters, glycolytic enzymes, and VEGF.

2. Research studies

Numerous studies show the decisive neuroprotective role that VEGF plays in the CNS. These include experiments where an intracerebroventricular administration of VEGF stimulates neurogenesis in the adult hippocampus, promotes neurites growth, or provides greater protection to motoneurons. Furthermore, it has also been shown that the retrograde transport of VEGF, after its intramuscular administration with lentiviral vectors, favors the survival of motoneurons. At the same time, the supply of VEGF at the site of a spinal cord injury decreases lesion size, apoptosis levels, and retards neurodegeneration.

Another protective effect of VEGF is also due to the induction of the expression of the GluA2 subunit in AMPA receptors, which leads to a reduction in the entry of Ca2+ in neurons, which is a relevant mechanism involved in motoneuronal degeneration. One of the mechanisms by which the binding of the VEGF-A isoform to the Flk-1 receptor improves and promotes cell survival is by blocking the process of apoptosis through the expression of anti-apoptotic proteins, such as the members of the Bcl-2 family and the generation of neuronal progenitors in the nervous system. VEGF binding to Flk-1 directly activates the PI3-K/Akt intracellular signaling pathway, causing an inhibition of the phosphorylation of p38MAPK, which is an essential factor in the cell death pathway, and an increase of the expression of the anti-apoptotic proteins Bcl-2 and A1, conceding greater protection to motoneurons against excitotoxicity. 

The ocular motoneurons present a series of morphological and functional characteristics that differentiate them from the rest of the motoneuronal populations. Several hypotheses have been proposed to explain the greater resistance of these cell populations to neurodegeneration.

Motoneurons of the ocular system show an extensive buffering capability of intracellular Ca2+ due to a greater expression of cytosolic Ca2+ binding proteins, such as calbindin D-28K (CaBP), calretinin (CR), and parvalbumin (PV). Notably, the extraocular motoneurons  also express a higher proportion of the insulin-like growth factor 2 (IGF-2), which acts as a survival factor for motoneurons. It has also been shown that receptor α1 of the inhibitory neurotransmitter GABA-A (Gabra1) is preferably present in resistant motoneurons, such as ocular motoneurons, of symptomatic SOD1 mice and patients with end-stage ALS. In contrast, vulnerable motoneurons show higher levels of GABA-A receptors α2 (Gabra2), dynein, and peripherin (intermediate neurofilament), which are involved in excitability and retrograde transport, which put these motoneurons at a higher risk. Another peculiarity of ocular motoneurons is that they express TrkA both in control and after axotomy in the adult, contrary to spinal motoneurons, giving them greater efficiency in their response to NGF, which acts as a potent survival factor for axotomized neonatal motoneurons. 

Remarkably, recently it has been shown that motoneurons of the oculomotor nuclei present higher expression of VEGF and Flk-1 in the motoneuronal soma compared to other more vulnerable groups of motoneurons, such as the facial and hypoglossal. Previous studies have also shown weak immunoreactivity for VEGF in hypoglossal and facial motoneurons in control rats. The neuroprotective role of VEGF could also contribute to the extended survival of ocular motoneurons in neurodegenerative diseases, such as ALS.


  1. Van Den Bosch, L.; Storkebaum, E.; Vleminckx, V.; Moons, L.; Vanopdenbosch, L.; Scheveneels, W.; Carmeliet, P.; Robberecht, W. Effects of vascular endothelial growth factor (VEGF) on motor neuron degeneration. Neurobiol. Dis. 2004, 17, 21–28.
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