Nature Genetics
28, 131 - 138 (2001)
doi:10.1038/88842
Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degenerationBert Oosthuyse1, Lieve Moons1, Erik Storkebaum1, Heike Beck2, Dieter Nuyens1, Koen Brusselmans1, Jo Van Dorpe3, Peter Hellings3, Marchel Gorselink4, Stéphane Heymans1, Gregor Theilmeier1, Mieke Dewerchin1, Vincent Laudenbach5, Patrick Vermylen3, Harold Raat6, Till Acker2, Vicky Vleminckx3, Ludo Van Den Bosch3, Neil Cashman7, Hajime Fujisawa8, Maarten R. Drost4, Raf Sciot3, Frans Bruyninckx3, Daniel J Hicklin9, Can Ince6, Pierre Gressens5, Florea Lupu10, Karl H. Plate2, Wim Robberecht3, Jean-Marc Herbert11, Désiré Collen1
& Peter Carmeliet11
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, B-3000, Belgium. 2
Department of Neuropathology, FAU Erlangen-Nürnberg, D-91054, Erlangen, Germany. 3
Faculty of Medicine, KU Leuven, Leuven, B-3000, Belgium. 4
CARIM, University of Maastricht, Maastricht, 6200 MD, The Netherlands. 5
INSERM E 9935 and Service de Neurologie Pédiatrique, Hôpital Robert-Debré, 4 8 BD Serurier; Paris F-75019, France. 6
Department of Anesthesiology, University of Amsterdam, Amsterdam, The Netherlands. 7
Centre for Research in Neurodegenerative Diseases, University of Toronto; Toronto Ontario, Canada M5S3H2. 8
Department of Molecular Biology, Nagoya University, Nagoya 464-01, Japan. 9
ImClone Systems Incorporated, New York, NY 10014. 10
Vascular Biology Laboratory, Thrombosis Research Institute, London SW3 6LR, UK. 11
Cardiovascular/thrombosis Research Department, Sanofi~Synthélabo, Toulouse, France.
Correspondence should be addressed to Peter Carmeliet peter.carmeliet@med.kuleuven.ac.beHypoxia 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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