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 Fujisawa; M R Drost; R Sciot; F Bruyninckx; D J Hicklin; C Ince; P Gressens; F Lupu; K H Plate; W Robberecht; J M Herbert; D Collen; P Carmeliet

doi:10.1038/88842

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

Nat Genet. 2001 Jun;28(2):131-8. doi: 10.1038/88842.

Affiliation

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

PMID: 11381259
DOI: 10.1038/88842

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / genetics
Amyotrophic Lateral Sclerosis / pathology
Animals
Axons / physiology
Binding Sites
Cell Hypoxia / genetics*
Electrophysiology
Endothelial Growth Factors / genetics*
Endothelial Growth Factors / metabolism
Humans
Lymphokines / genetics*
Lymphokines / metabolism
Mice
Mice, Knockout
Motor Neurons / pathology*
Motor Neurons / physiology
Muscle Contraction
Muscle Fibers, Skeletal / pathology
Muscular Atrophy / genetics
Muscular Atrophy / pathology
Nerve Degeneration / genetics*
Nerve Degeneration / pathology
Nerve Degeneration / physiopathology
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Neuropilin-1
Peripheral Nerves / pathology
Promoter Regions, Genetic
Receptor Protein-Tyrosine Kinases / genetics
Receptor Protein-Tyrosine Kinases / metabolism
Receptors, Growth Factor / genetics
Receptors, Growth Factor / metabolism
Receptors, Vascular Endothelial Growth Factor
Response Elements / genetics*
Sequence Deletion
Spinal Cord / physiology
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors

Substances

Endothelial Growth Factors
Lymphokines
Nerve Tissue Proteins
Receptors, Growth Factor
VEGFA protein, human
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Neuropilin-1
Receptor Protein-Tyrosine Kinases
Receptors, Vascular Endothelial Growth Factor