RGD Reference Report - Hypoxia and hypoxia-inducible factor-1 target genes in central nervous system radiation injury: a role for vascular endothelial growth factor. - Rat Genome Database

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Hypoxia and hypoxia-inducible factor-1 target genes in central nervous system radiation injury: a role for vascular endothelial growth factor.

Authors: Nordal, RA  Nagy, A  Pintilie, M  Wong, CS 
Citation: Nordal RA, etal., Clin Cancer Res. 2004 May 15;10(10):3342-53.
RGD ID: 9068912
Pubmed: PMID:15161688   (View Abstract at PubMed)
DOI: DOI:10.1158/1078-0432.CCR-03-0426   (Journal Full-text)

PURPOSE: Microvascular permeability changes and loss of blood-brain barrier integrity are important features of central nervous system (CNS) radiation injury. Expression of vascular endothelial growth factor (VEGF), an important determinant of microvascular permeability, was examined to assess its role in CNS radiation damage. Because hypoxia mediates VEGF up-regulation through hypoxia-inducible factor-1alpha (HIF1alpha) induction, we studied the relationships of hypoxia, HIF1alpha expression, and expression of VEGF in this damage pathway. EXPERIMENTAL DESIGN: Expression of HIF1alpha, VEGF, and another hypoxia-responsive gene, glucose transporter-1, was assessed in the irradiated rat spinal cord using immunohistochemistry and in situ hybridization. Hypoxic areas were identified using the nitroimidazole 2-(2-nitro-1H-imidazole-L-yl)-N-(2,2,3,3,3,-pentafluoropropyl) acetamide. To determine the causal importance of VEGF expression in radiation myelopathy, we studied the response of transgenic mice with greater (VEGF-A(hi/+)), reduced (VEGF-A(lo/+)), and wild-type VEGF activity to thoracolumbar irradiation. RESULTS: In rat spinal cord, the number of cells expressing HIF1alpha and VEGF increased rapidly from 16 to 20 weeks after radiation, before white matter necrosis and forelimb paralysis. A steep dose response was observed in expression of HIF1alpha and VEGF. HIF1alpha and VEGF expressing cells were identified as astrocytes. Hypoxia was present in regions where up-regulation of VEGF and glucose transporter-1 and increased permeability was observed. VEGF-A(lo/+) mice had a longer latency to development of hindlimb weakness and paralysis compared with wild-type or VEGF-A(hi/+) mice. CONCLUSIONS: VEGF expression appears to play an important role in CNS radiation injury. This focuses attention on VEGF and other genes induced in response to hypoxia as targets for therapy to reduce or prevent CNS radiation damage.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HIF1AHumanExperimental Radiation Injuries  ISOHif1a (Rattus norvegicus)protein:increased expression:white matter of spinal cord (rat)RGD 
Hif1aRatExperimental Radiation Injuries  IEP protein:increased expression:white matter of spinal cord (rat)RGD 
Hif1aMouseExperimental Radiation Injuries  ISOHif1a (Rattus norvegicus)protein:increased expression:white matter of spinal cord (rat)RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Hif1aRatresponse to X-ray  IEP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hif1a  (hypoxia inducible factor 1 subunit alpha)

Genes (Mus musculus)
Hif1a  (hypoxia inducible factor 1, alpha subunit)

Genes (Homo sapiens)
HIF1A  (hypoxia inducible factor 1 subunit alpha)


Additional Information