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

B. Oosthuyse, L. Moons, E. Storkebaum, H. Beck, D. Nuyens, K. Brusselmans, J. van Dorpe, P. Hellings, M. Gorselink, S. Heymans, G Theilmeier, M. Dewerchin, V. Laudenbach, P. Vermylen, H. Raat, T. Acker, V. Vleminckx, L. van den Bosch, N. Cashman, H. FujisawaM. Drost, R. Sciot, F. Bruyninckx, Daniel J. Hicklin, C. Ince, P. Gressens, F. Lupu, K.H. Plate, W. Robberecht, J.M. Herbert, D. Collen, P. Carmeliet

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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. Vegf(165) 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.
Original languageEnglish
Pages (from-to)131-138
Number of pages8
JournalNature Genetics
Volume28
Issue number2
DOIs
Publication statusPublished - 1 Jan 2001

Cite this

Oosthuyse, B., Moons, L., Storkebaum, E., Beck, H., Nuyens, D., Brusselmans, K., van Dorpe, J., Hellings, P., Gorselink, M., Heymans, S., Theilmeier, G., Dewerchin, M., Laudenbach, V., Vermylen, P., Raat, H., Acker, T., Vleminckx, V., van den Bosch, L., Cashman, N., ... Carmeliet, P. (2001). Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nature Genetics, 28(2), 131-138. https://doi.org/10.1038/88842