Vascular Endothelial Growth Factor (VEGF) Prevents the Downregulation of the Cholinergic Phenotype in Axotomized Motoneurons of the Adult Rat

Abstract

Vascular endothelial growth factor (VEGF) was initially characterized by its activity on the vascular system. However, there is growing evidence indicating that VEGF also acts as a neuroprotective factor, and that its administration to neurons suffering from trauma or disease is able to rescue them from cell death. We questioned whether VEGF could also maintain damaged neurons in a neurotransmissive mode by evaluating the synthesis of their neurotransmitter, and whether its action would be direct or through its well-known angiogenic activity. Adult rat extraocular motoneurons were chosen as the experimental model. Lesion was performed by monocular enucleation and immediately a gelatine sponge soaked in VEGF was implanted intraorbitally. After 7 days, abducens, trochlear, and oculomotor nuclei were examined by immunohistochemistry against choline acetyltransferase (ChAT), the biosynthetic enzyme of the motoneuronal neurotransmitter acetylcholine. Lesioned motoneurons exhibited a noticeable ChAT downregulation which was prevented by VEGF administration. To explore whether this action was mediated via an increase in blood vessels or in their permeability, we performed immunohistochemistry against laminin, glucose transporter-1 and the plasmatic protein albumin. The quantification of the immunolabeling intensity against these three proteins showed no significant differences between VEGF-treated, axotomized and control animals. Therefore, the present data indicate that VEGF is able to sustain the cholinergic phenotype in damaged motoneurons, which is a first step for adequate neuromuscular neurotransmission, and that this action seems to be mediated directly on neurons since no sign of angiogenic activity was evident. These data reinforces the therapeutical potential of VEGF in motoneuronal diseases.

Limited Impact of Human Cytomegalovirus Infection in African Infants on Vaccine-Specific Responses Following Diphtheria-Tetanus-Pertussis and Measles Vaccination

“…The lack of impact of HCMV infection on measles-specific innate pro-inflammatory cytokines IL-1β and TNF, the Th1 cytokine IFN-γ, the Th2 cytokine IL-4 and the anti-inflammatory cytokine IL-10 is encouraging. The clinical significance of lower VEGF production is uncertain but it is an important vascular growth factor that has also been linked with trauma and malignancy (39,40). Effects on tetanus toxoid-specific responses similarly showed lower GMCSF and eotaxin in the HCMV+ infants but no effect on innate pro-inflammatory, Th1, Th2 cytokines or IL-10.…”

Neuroprotective Effect of Vascular Endothelial Growth Factor on Motoneurons of the Oculomotor System

“…It is well-known that VEGF also acts as a growth factor for vascular endothelial cells forming the blood vessels [ 2 ], promoting vascular proliferation and permeability and therefore providing oxygen and nutrients to neurons, which contribute to their wellness. Administration of exogenous VEGF in the brainstem is not accompanied by either angiogenesis or a significantly increased vascular permeability around treated motoneurons [ 164 ]. Therefore, it could be assumed that the action of this factor on motoneuron survival was likely due to a direct effect on the motoneurons instead of an indirect effect due to increased blood perfusion.…”

“…Therefore, it could be assumed that the action of this factor on motoneuron survival was likely due to a direct effect on the motoneurons instead of an indirect effect due to increased blood perfusion. Besides, no differences were observed in the vascularization of these motor nuclei, neither in control nor after an injury [ 151 , 164 ].…”

“…Previous studies showed changes in the expression of other trophic factors, such as neurotrophins, or their receptors in motoneurons after axotomy [ 120 , 132 , 179 ]. It has also been described that axotomized motoneurons experience a decrease in the expression of the protein acetylcholintransferase (ChAT) [ 120 , 132 , 164 ]. It is important to note that both the immunoreactivity of ChAT and the activity and mRNA of this enzyme are also markedly reduced in cases of ALS [ 180 , 181 , 182 ].…”

“…In fact, the motoneurons of the anterior horn of the spinal cord suffer a decrease in ChAT activity from early stages, compared to control neurons [ 183 ], which suggests that a reduction in ChAT expression is a specific and initial change in disease pathogenesis [ 184 ]. It is worth mentioning that the exogenous administration of VEGF at the site of the injury is capable of preventing the loss of the cholinergic phenotype in the axotomized motoneurons, which allows the ocular motoneurons to retain a neurotransmissive phenotype [ 164 ]. These studies emphasize the importance of the neuroprotective effect that VEGF has on motoneurons by maintaining its synaptic transmission capacity.…”