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Sources and lesion-induced changes of VEGF expression in brainstem motoneurons

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Abstract

Motoneurons of the oculomotor system show lesser vulnerability to neurodegeneration compared to other cranial motoneurons, as seen in amyotrophic lateral sclerosis (ALS). The overexpression of vascular endothelial growth factor (VEGF) is involved in motoneuronal protection. As previously shown, motoneurons innervating extraocular muscles present a higher amount of VEGF and its receptor Flk-1 compared to facial or hypoglossal motoneurons. Therefore, we aimed to study the possible sources of VEGF to brainstem motoneurons, such as glial cells and target muscles. We also studied the regulation of VEGF in response to axotomy in ocular, facial, and hypoglossal motor nuclei. Basal VEGF expression in astrocytes and microglial cells of the cranial motor nuclei was low. Although the presence of VEGF in the different target muscles for brainstem motoneurons was similar, the presynaptic element of the ocular neuromuscular junction showed higher amounts of Flk-1, which could result in greater efficiency in the capture of the factor by oculomotor neurons. Seven days after axotomy, a clear glial reaction was observed in all the brainstem nuclei, but the levels of the neurotrophic factor remained low in glial cells. Only the injured motoneurons of the oculomotor system showed an increase in VEGF and Flk-1, but such an increase was not detected in axotomized facial or hypoglossal motoneurons. Taken together, our findings suggest that the ocular motoneurons themselves upregulate VEGF expression in response to lesion. In conclusion, the low VEGF expression observed in glial cells suggests that these cells are not the main source of VEGF for brainstem motoneurons. Therefore, the higher VEGF expression observed in motoneurons innervating extraocular muscles is likely due either to the fact that this factor is more avidly taken up from the target muscles, in basal conditions, or is produced by these motoneurons themselves, and acts in an autocrine manner after axotomy.

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Acknowledgements

Confocal microscopy imaging was performed in the central research services of the Universidad de Sevilla (CITIUS). This work was supported by the Ministerio de Economía y Competitividad (Grant reference: BFU2015-64515-P and PGC2018-094654-B-100) and Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía, BIO-297, in Spain. Confocal images were performed in the Central Research Services of University of Sevilla (CITIUS). We acknowledge Dr. Paul J May from UMMC for helpful comments and editing the manuscript.

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  1. Departamento de Fisiología, Facultad de Biología, Universidad de Sevilla, Seville, Spain

    Silvia Silva-Hucha, Génova Carrero-Rojas, María Estrella Fernández de Sevilla, Beatriz Benítez-Temiño, María América Davis-López de Carrizosa, Angel M. Pastor & Sara Morcuende

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  1. Silvia Silva-Hucha
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  2. Génova Carrero-Rojas
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Contributions

SM, SSH, AMP, MADLC, and BBT designed the experiments. SM, SSH, BBT, GCR, MEFS, and AMP performed the experiments. SM, SSH, and BBT analyzed and processed the data. SM wrote the manuscript. SM, AMP, MADLC, and BBT proofread and edited the manuscript. All the authors read and approved the final version of the manuscript.

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Correspondence to Sara Morcuende.

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Silva-Hucha, S., Carrero-Rojas, G., Fernández de Sevilla, M.E. et al. Sources and lesion-induced changes of VEGF expression in brainstem motoneurons. Brain Struct Funct 225, 1033–1053 (2020). https://doi.org/10.1007/s00429-020-02057-y

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