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Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration

Nature Genetics volume 28, pages 131–138 (2001)Cite this article

Abstract

Hypoxia stimulates angiogenesis through the binding of hypoxia-inducible factors to the hypoxia-response element in the vascular endothelial growth factor (Vegf) promotor. Here, we report that deletion of the hypoxia-response element in the Vegf promotor reduced hypoxic Vegf expression in the spinal cord and caused adult-onset progressive motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis. The neurodegeneration seemed to be due to reduced neural vascular perfusion. In addition, Vegf165 promoted survival of motor neurons during hypoxia through binding to Vegf receptor 2 and neuropilin 1. Acute ischemia is known to cause nonselective neuronal death. Our results indicate that chronic vascular insufficiency and, possibly, insufficient Vegf-dependent neuroprotection lead to the select degeneration of motor neurons.

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Figure 1: Muscle weakness in Vegf∂/∂ mice.
Figure 2: Motor neuron degeneration in Vegf∂/∂ mice.
Figure 3: Axon degeneration in Vegf∂/∂ mice.
Figure 4: Expression of Vegf and receptors in the spinal cord.
Figure 5: Neurotrophic function of Vegf.

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Acknowledgements

We thank F. Bono (Synthélabo), S. Thom (Erlangen), A. Westmuckett and D. Goulding (London), and K. Bijnens, A. Bouché, S. De Cat, M. De Mol, I. Cartois, K. De Roover, E. Gils, B. Hermans, S. Jansen, L. Kieckens, Y.W. Man, A. Manderveld, K. Maris, A. Sahli, T. Vancoetsem, A. Vandenhoeck, P. Vanwesemael, B. Vanwetswinkel and S. Wyns (CTG, Belgium) for assistance. This work was supported by the European Community (Biomed BMH4-CT98-3380), Actie Levenslijn (#7.0019.98), FWO (G012500) and the Schwerpunktprogramm 1069 Angiogenese (GFG Pl 158-4/1). G.T. is a postdoctoral fellow of the DFG (Germany) B.O. is a fellow of the IWT, and L.V.D.B. is a postdoctoral fellow and W.R. is a clinical investigator of the FWO. This work was supported by GOA/93/03.

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Authors and Affiliations

  1. The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, B-3000, Leuven, Belgium

    Bert Oosthuyse, Lieve Moons, Erik Storkebaum, Dieter Nuyens, Koen Brusselmans, Stéphane Heymans, Gregor Theilmeier, Mieke Dewerchin, Désiré Collen & Peter Carmeliet

  2. Department of Neuropathology, FAU Erlangen-Nürnberg, Erlangen, D-91054, Germany

    Heike Beck, Till Acker & Karl H. Plate

  3. Faculty of Medicine, KU Leuven, B-3000, Leuven, Belgium

    Jo Van Dorpe, Peter Hellings, Patrick Vermylen, Vicky Vleminckx, Ludo Van Den Bosch, Raf Sciot, Frans Bruyninckx & Wim Robberecht

  4. CARIM, University of Maastricht, Maastricht, 6200 MD, The Netherlands

    Marchel Gorselink & Maarten R. Drost

  5. INSERM E 9935 and Service de Neurologie Pédiatrique, Hôpital Robert-Debré, 4 8 BD Serurier

    Vincent Laudenbach & Pierre Gressens

  6. Paris, F-75019, France

    Vincent Laudenbach & Pierre Gressens

  7. Department of Anesthesiology, University of Amsterdam, Amsterdam, The Netherlands

    Harold Raat & Can Ince

  8. Centre for Research in Neurodegenerative Diseases, University of Toronto,

    Neil Cashman

  9. Toronto, M5S3H2, Ontario, Canada

    Neil Cashman

  10. Department of Molecular Biology, Nagoya University, Nagoya, 464-01, Japan

    Hajime Fujisawa

  11. ImClone Systems Incorporated, New York, 10014, NY

    Daniel J Hicklin

  12. Vascular Biology Laboratory, Thrombosis Research Institute, London, SW3 6LR, UK

    Florea Lupu

  13. Cardiovascular/thrombosis Research Department, Sanofi˜Synthélabo, Toulouse, France

    Jean-Marc Herbert

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Correspondence to Peter Carmeliet.

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Oosthuyse, B., Moons, L., Storkebaum, E. et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 28, 131–138 (2001). https://doi.org/10.1038/88842

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