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Vascular endothelial growth factor: a neurovascular target in neurological diseases

Key Points

  • Vascular endothelial growth factor (VEGF) has been implicated in the aetiology and treatment of various neurological diseases

  • VEGF exerts effects on multiple cell types in the nervous system, including endothelial cells, neurons, astrocytes, microglia, oligodendrocytes and Schwann cells

  • VEGF protects neurons and fosters neurogenesis, and reduced VEGF levels contribute to neurodegenerative disorders

  • VEGF can improve brain perfusion, partly by promoting angiogenesis, but pathological VEGF levels induce blood–brain barrier breakdown and vessel leakage

  • Preclinical studies indicate that VEGF administration is beneficial in neurodegenerative diseases, peripheral neuropathies and epilepsy

  • VEGF inhibition is approved as a treatment for neovascular ocular diseases, and might be beneficial in other neurological disorders involving BBB breakdown or excessive angiogenesis

Abstract

Brain function critically relies on blood vessels to supply oxygen and nutrients, to establish a barrier for neurotoxic substances, and to clear waste products. The archetypal vascular endothelial growth factor, VEGF, arose in evolution as a signal affecting neural cells, but was later co-opted by blood vessels to regulate vascular function. Consequently, VEGF represents an attractive target to modulate brain function at the neurovascular interface. On the one hand, VEGF is neuroprotective, through direct effects on neural cells and their progenitors and indirect effects on brain perfusion. In accordance, preclinical studies show beneficial effects of VEGF administration in neurodegenerative diseases, peripheral neuropathies and epilepsy. On the other hand, pathologically elevated VEGF levels enhance vessel permeability and leakage, and disrupt blood–brain barrier integrity, as in demyelinating diseases, for which blockade of VEGF may be beneficial. Here, we summarize current knowledge on the role and therapeutic potential of VEGF in neurological diseases.

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Figure 1: The VEGF family of growth factors.
Figure 2: VEGF in the CNS.
Figure 3: VEGF in neurodegenerative disease.
Figure 4: Vasa nervorum loss in diabetic peripheral neuropathy.
Figure 5: Role of VEGF in stroke.
Figure 6: Vascular dysfunction in epilepsy.
Figure 7: VEGF as a mediator of neuroinflammatory disease.

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Acknowledgements

C.L. is a postdoctoral fellow of the Fonds Wetenschappelijk Onderzoek (FWO). E.S. is supported by funding from the Max Planck Society, the state of North Rhine-Westphalia, the Frick Foundation for ALS Research, the Minna James Heineman Foundation and the French Muscular Dystrophy Association (AFM). C.R.d.A. is supported by grants ERC-StG-311367, FP7-PEOPLE-2011-CIG-304054 and DFG-FOR 2325, and the Schram Foundation. M.D. is supported by the Belgian Science Policy (grants IAP-P6/20 and IAP-P7/20). P.C. is supported by the Belgian Science Policy (grant IAP-P7/03), long-term structural Methusalem funding from the Flemish Government, grants from the FWO (G.0595.12N, 1.5.149.13N and 1.5.211.14N), the Foundation Leducq Transatlantic Network (ARTEMIS), the 'A cure for ALS' fund from the ALS League Belgium, the Motor Neuron Disease Association, the ALS Association (ID#C44128), Euro-MOTOR (EU HEALTH project), and the Leuven University Fund — Opening the Future.

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P.C. is named as inventor on patent applications WO 01/76620 and WO 2005/117946 and applicable resulting patents, which relate to results described in this article. The aforementioned patent application has been licensed, which may result in a royalty payment to P.C. The other authors declare no competing interests.

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Lange, C., Storkebaum, E., de Almodóvar, C. et al. Vascular endothelial growth factor: a neurovascular target in neurological diseases. Nat Rev Neurol 12, 439–454 (2016). https://doi.org/10.1038/nrneurol.2016.88

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