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Molecular Neurobiology

, Volume 55, Issue 5, pp 3611–3626 | Cite as

Vascular Endothelial Growth Factor Isoform-B Stimulates Neurovascular Repair After Ischemic Stroke by Promoting the Function of Pericytes via Vascular Endothelial Growth Factor Receptor-1

  • Noëmie Jean LeBlanc
  • Revathy Guruswamy
  • Ayman ElAli
Article

Abstract

Ischemic stroke triggers endogenous angiogenic mechanisms, which correlates with longer survival in patients. As such, promoting angiogenesis appears to be a promising approach. Experimental studies investigated mostly the potent angiogenic factor vascular endothelial growth factor isoform-A (VEGF-A). However, VEGF-A increases the risk of destabilizing the brain microvasculature, thus hindering the translation of its usage in clinics. An attractive alternative VEGF isoform-B (VEGF-B) was recently reported to act as a survival factor rather than a potent angiogenic factor. In this study, we investigated the therapeutic potential of VEGF-B in ischemic stroke using different in vivo and in vitro approaches. We showed that the delayed intranasal administration of VEGF-B reduced neuronal damage and inflammation. Unexpectedly, VEGF-B stimulated the formation of stable brain microvasculature within the injured region by promoting the interaction between endothelial cells and pericytes. Our data indicate that the effects of VEGF-B were mediated via its specific receptor VEGF receptor-1 (VEGFR-1) that is predominately expressed in brain pericytes. Importantly, VEGF-B promoted the survival of pericytes, and not brain endothelial cells, by inducing expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and the main protein involved in energy homeostasis AMP-activated protein kinase α (AMPKα). Moreover, we showed that VEGF-B stimulated the pericytic release of factors stimulating a “reparative angiogenesis” that does not compromise microvasculature stability. Our study unraveled hitherto unknown role of VEGF-B/VEGFR-1 signaling in regulating the function of pericytes. Furthermore, our findings suggest that brain microvasculature stabilization via VEGF-B constitutes a safe therapeutic approach for ischemic stroke.

Keywords

Stroke Repair Pericytes Endothelial cells Angiogenesis VEGF-B VEGFR-1 

Notes

Acknowledgments

This work was supported by grants from the Fondation du CHU de Québec (2331) and Merck-Faculty of Medicine, Laval University. NJL is supported by a scholarship from the Fondation du CHU de Québec and the Faculty of Medicine, Laval University.

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Noëmie Jean LeBlanc
    • 1
  • Revathy Guruswamy
    • 1
  • Ayman ElAli
    • 1
  1. 1.Neuroscience Axis, CHU de Québec Research Center (CHUL) and Department of Psychiatry and Neuroscience, Faculty of MedicineLaval UniversityQuebec CityCanada

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