Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration.
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.
Oosthuyse
B
B
The Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, B-3000, Belgium.
Moons
L
L
Storkebaum
E
E
Beck
H
H
Nuyens
D
D
Brusselmans
K
K
Van Dorpe
J
J
Hellings
P
P
Gorselink
M
M
Heymans
S
S
Theilmeier
G
G
Dewerchin
M
M
Laudenbach
V
V
Vermylen
P
P
Raat
H
H
Acker
T
T
Vleminckx
V
V
Van Den Bosch
L
L
Cashman
N
N
Fujisawa
H
H
Drost
M R
MR
Sciot
R
R
Bruyninckx
F
F
Hicklin
D J
DJ
Ince
C
C
Gressens
P
P
Lupu
F
F
Plate
K H
KH
Robberecht
W
W
Herbert
J M
JM
Collen
D
D
Carmeliet
P
P
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology; D000818:Animals; D001369:Axons / Q000502:physiology; D001665:Binding Sites; D015687:Cell Hypoxia / Q000235:genetics*; D004594:Electrophysiology; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000473:pathology* / Q000502:physiology; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D039942:Neuropilin-1; D010525:Peripheral Nerves / Q000473:pathology; D011401:Promoter Regions, Genetic; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D020218:Response Elements / Q000235:genetics*; D017384:Sequence Deletion; D013116:Spinal Cord / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D039942:Neuropilin-1; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor