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.
Highlights
Vascular endothelial growth factor (VEGF) was initially characterized by its actions on the vasculature, inducing vasculogenesis, angiogenesis and increased permeability of capillary vessels (Ferrara and Davis-Smyth, 1997; Yancopoulos et al, 2000)
The present work has demonstrated that the exogenous administration of VEGF is able to maintain injured motoneurons with a normal level of choline acetyltransferase (ChAT), the biosynthetic enzyme of their neurotransmitter acetylcholine, thereby preventing the downregulation in ChAT that ensues motoneuronal lesion
The fact that ChAT can be maintained in axotomized VEGF-treated motoneurons likely implies a normal level of the motoneuronal neurotransmitter acetylcholine
Summary
Vascular endothelial growth factor (VEGF) was initially characterized by its actions on the vasculature, inducing vasculogenesis, angiogenesis and increased permeability of capillary vessels (Ferrara and Davis-Smyth, 1997; Yancopoulos et al, 2000). The delivery of VEGF directly or through viral vectors using different routes (intramuscular, intracerebroventricular, intrathecal or into the spinal cord parenchyma) considerably reduces the symptoms of the disease in murine models of ALS (Azzouz et al, 2004; Storkebaum et al, 2005; Dodge et al, 2010; Wang et al, 2016) and protects motoneurons from excitotoxic-induced cell death (Tovar-y-Romo et al, 2007; Tovar-y-Romo and Tapia, 2010) In this respect, an increase in VEGF and its main receptor (VEGFR-2) has been described in cerebral motor cortex and hippocampus of postnatal rats following glutamate excitotoxic treatment, which could contribute to neuroprotection mechanisms (Castañeda-Cabral et al, 2017)
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