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

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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, 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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Correspondence to Peter Carmeliet.

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