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.

[1]  R. Liem.  Neuronal intermediate filaments. , 1990, Current opinion in cell biology.

[2]  Robert H. Brown,et al.  Increased 3‐nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis , 1997, Annals of neurology.

[3]  N. van Bruggen,et al.  VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. , 1999, The Journal of clinical investigation.

[4]  Willem Flameng,et al.  Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188 , 1999, Nature Medicine.

[5]  T. Tabira,et al.  Neuroblastoma × spinal cord (NSC) hybrid cell lines resemble developing motor neurons , 1992, Developmental dynamics : an official publication of the American Association of Anatomists.

[6]  A. Levy,et al.  Hypoxic Stabilization of Vascular Endothelial Growth Factor mRNA by the RNA-binding Protein HuR* , 1998, The Journal of Biological Chemistry.

[7]  E. Goldwasser,et al.  A new transacting factor that modulates hypoxia-induced expression of the erythropoietin gene. , 2000, Blood.

[8]  Shay Soker,et al.  Neuropilin-1 Is Expressed by Endothelial and Tumor Cells as an Isoform-Specific Receptor for Vascular Endothelial Growth Factor , 1998, Cell.

[9]  W. Jelkmann,et al.  Interleukin-1beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1. , 1999, Blood.

[10]  P. Carmeliet.  Mechanisms of angiogenesis and arteriogenesis , 2000, Nature Medicine.

[11]  Jonathan A Raper,et al.  Semaphorins and their receptors in vertebrates and invertebrates , 2000, Current Opinion in Neurobiology.

[12]  G. Semenza.  Expression of hypoxia-inducible factor 1: mechanisms and consequences. , 2000, Biochemical pharmacology.

[13]  W. Risau,et al.  Systemic hypoxia changes the organ-specific distribution of vascular endothelial growth factor and its receptors. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[14]  Lieve Moons,et al.  Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele , 1996, Nature.

[15]  G. Semenza,et al.  Age-dependent Defect in Vascular Endothelial Growth Factor Expression Is Associated with Reduced Hypoxia-inducible Factor 1 Activity* , 2000, The Journal of Biological Chemistry.

[16]  A. Shaikh,et al.  Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (Review). , 2000, International journal of molecular medicine.

[17]  L. WilliamsonT,et al.  神経フィラメントの欠如は,家族性筋萎縮性側索硬化症関連スーパオキジドジスムターゼ1変異に対する運動ニューロンの選択的易損性を低下させ,疾患を遅らせる , 1998 .

[18]  M. Gurney,et al.  Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. , 1994, The American journal of pathology.

[19]  Y. Dor,et al.  Ischemia-driven angiogenesis. , 1997, Trends in cardiovascular medicine.

[20]  Y. Takeuchi,et al.  Immunohistochemical nitrotyrosine distribution in neonatal rat cerebrocortical slices during and after hypoxia , 1999, Brain Research.

[21]  M. Bromberg.  Pathogenesis of amyotrophic lateral sclerosis: a critical review. , 1999, Current opinion in neurology.

[22]  W. Jelkmann,et al.  Interleukin-1β and Tumor Necrosis Factor- Stimulate DNA Binding of Hypoxia-Inducible Factor-1 , 1999 .

[23]  S. Soker,et al.  Neuropilin-1 Mediates Collapsin-1/Semaphorin III Inhibition of Endothelial Cell Motility , 1999, The Journal of cell biology.

[24]  A. Kolodkin,et al.  Semaphorin Signaling A Little Less Per-Plexin , 1999, Neuron.

[25]  Robert H. Brown,et al.  Evidence of Increased Oxidative Damage in Both Sporadic and Familial Amyotrophic Lateral Sclerosis , 1997, Journal of neurochemistry.

[26]  Sakurai,et al.  Expression of angiogenic factors in rabbit spinal cord after transient ischaemia , 1999, Neuropathology and applied neurobiology.

[27]  Accurate assessment of in situ isometric contractile properties of hindlimb plantar and dorsal flexor muscle complex of intact mice , 2000, Pflügers Archiv.

[28]  G. Lundborg,et al.  Vascular Endothelial Growth Factor Has Neurotrophic Activity and Stimulates Axonal Outgrowth, Enhancing Cell Survival and Schwann Cell Proliferation in the Peripheral Nervous System , 1999, The Journal of Neuroscience.

[29]  J. Alroy,et al.  Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy , 2000, Nature Medicine.

[30]  W. Robberecht,et al.  Evolution of motor and sensory deficits in amyotrophic lateral sclerosis estimated by neurophysiological techniques , 1999, Journal of Neurology.

[31]  M. Gurney,et al.  Midbrain dopaminergic neuronal degeneration in a transgenic mouse model of familial amyotrophic lateral sclerosis , 1997, Annals of neurology.

[32]  Napoleone Ferrara,et al.  Clinical applications of angiogenic growth factors and their inhibitors , 1999, Nature Medicine.

[33]  P. Einat,et al.  Translation of Vascular Endothelial Growth Factor mRNA by Internal Ribosome Entry: Implications for Translation under Hypoxia , 1998, Molecular and Cellular Biology.

[34]  C. Aring,et al.  A CRITICAL REVIEW , 1939, Journal of neurology and psychiatry.

[35]  R. Tolwani,et al.  Animal models for motor neuron disease. , 1999, Laboratory animal science.

[36]  J. Kong,et al.  Massive Mitochondrial Degeneration in Motor Neurons Triggers the Onset of Amyotrophic Lateral Sclerosis in Mice Expressing a Mutant SOD1 , 1998, The Journal of Neuroscience.

[37]  K. Jin,et al.  Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[38]  P. Dyck,et al.  LUMBAR MOTONEURONS OF MAN: I) NUMBER AND DIAMETER HISTOGRAM OF ALPHA AND GAMMA AXONS OF VENTRAL ROOT , 1977, Journal of neuropathology and experimental neurology.

[39]  P Lavie,et al.  Interindividual heterogeneity in the hypoxic regulation of VEGF: significance for the development of the coronary artery collateral circulation. , 1999, Circulation.

[40]  K. Plate,et al.  Cell type specific upregulation of vascular endothelial growth factor in an MCA-occlusion model of cerebral infarct. , 1999, Journal of neuropathology and experimental neurology.

[41]  J. Knight.  Reactive oxygen species and the neurodegenerative disorders. , 1997, Annals of clinical and laboratory science.

[42]  W. Robberecht,et al.  Glial cells potentiate kainate-induced neuronal death in a motoneuron-enriched spinal coculture system , 1998, Brain Research.

[43]  Q. Zhu,et al.  Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[44]  M. Tessier-Lavigne,et al.  Neuropilin Is a Receptor for the Axonal Chemorepellent Semaphorin III , 1997, Cell.

[45]  W. Stewart,et al.  Neuronal VEGF expression correlates with angiogenesis in postnatal developing rat brain. , 2000, Brain research. Developmental brain research.

[46]  W. Risau,et al.  Activator-protein-1 binding potentiates the hypoxia-induciblefactor-1-mediated hypoxia-induced transcriptional activation of vascular-endothelial growth factor expression in C6 glioma cells. , 1997, The Biochemical journal.

[47]  M. Moskowitz,et al.  Spinal cord ischemia. Development of a model in the mouse. , 2000, Stroke.

[48]  L. Gille,et al.  Imbalance of oxygen activation and energy metabolism as a consequence or mediator of aging , 1997, Experimental Gerontology.