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VEGF-A Promotes Both Pro-angiogenic and Neurotrophic Capacities for Nerve Recovery After Compressive Neuropathy in Rats

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Abstract

Nerve recovery following injury is usually incomplete, leaving functional deficits. Our aim was to investigate the neural changes in pro-angiogenic, pro-inflammatory and apoptotic factors during and after chronic nerve compression (CNC). Nerve function was impaired after CNC and was progressively restored after nerve decompression, while nerve blood flow was elevated. While the expression of the pro-inflammatory and pro-angiogenic cytokines IL-6, TNF-α and VEGF-A was high during and after CNC, we observed that inhibition of VEGF-A receptors strongly counteracted the angiogenic response induced by the ex vivo CNC. Activation of the pro-survival transcription factor nuclear factor-kappa B (NF–κB) increased during CNC, returning to control levels after nerve decompression. After nerve decompression, the downregulation of Mdm2 correlated well with an increased expression of pro-apoptotic transcription factor p53. All together, we bring novel evidence that CNC activates transcription factors such as NF–κB and p53, which are key effectors of the cellular stress response, suggesting a neuroprotective process associated with an increased VEGF-A-mediated neurotrophic effect. Our results highlight the role of pro-angiogenic and pro-inflammatory cytokines during CNC that are reinforced by increasing neurotrophic capacity during recovery to promote nerve regeneration.

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Acknowledgments

This study was funded by ANR grant ANR-07-SEST-01601. Julien Pelletier was supported by a grant from the French Ministère de l’Enseignement Supérieur et de la Recherche (University of Lyon 1, EDISS) and by a grant from the Rhônes-Alpes Region (CMIRA EXPLORA’DOC 2009). Research in the Angiogenesis Research Group is funded by the Natural Sciences and Engineering Research Council of Canada (NSERC DG 341258-2011 to Olivier Birot). We thank Mrs. Patricia Hulmes for editorial assistance. We would like to thank Virginie Briffaud for help assistance in manuscript.

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Authors and Affiliations

  1. IBCP–UMR 5305 CNRS, 7 passage du Vercors, 69 367, Lyon Cedex 07, France

    Julien Pelletier, Bérengère Fromy, Jean Louis Saumet & Dominique Sigaudo-Roussel

  2. University of Lyon 1, 69 367, Lyon Cedex 07, France

    Julien Pelletier, Bérengère Fromy, Jean Louis Saumet & Dominique Sigaudo-Roussel

  3. Faculty of Health, Angiogenesis Research Group, York University, Toronto, M3J 1P3, Canada

    Julien Pelletier, Emilie Roudier & Olivier Birot

  4. Laboratory of Vascular Investigations, University Hospital of Angers, Angers, France

    Pierre Abraham

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  1. Julien Pelletier
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Pelletier, J., Roudier, E., Abraham, P. et al. VEGF-A Promotes Both Pro-angiogenic and Neurotrophic Capacities for Nerve Recovery After Compressive Neuropathy in Rats. Mol Neurobiol 51, 240–251 (2015). https://doi.org/10.1007/s12035-014-8754-1

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