title: Hypoxia and hypoxia-inducible factor-1 target genes in central nervous system radiation injury: a role for vascular endothelial growth factor.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Radiation Oncology, Sunnybrook and Women's College Health Sciences Center, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Nordal
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.forename: C Shun
authors.initials: CS
authors.lastname: Wong
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002490:Central Nervous System / Q000528:radiation effects*; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009336:Necrosis; D009687:Nuclear Proteins / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013116:Spinal Cord / Q000378:metabolism / Q000528:radiation effects; D013119:Spinal Cord Injuries / Q000473:pathology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D012313:RNA