Hypoxia and Hypoxia-Inducible Factor-1 Target Genes in Central Nervous System Radiation Injury

Abstract

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-1␣ (HIF1␣) induction, we studied the relationships of hypoxia, HIF1␣ expression, and expression of VEGF in this damage pathway.Experimental Design: Expression of HIF1␣, 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,- 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.

Permeability Estimates in Histopathology-Proved Treatment-Induced Necrosis Using Perfusion CT: Can These Add to Other Perfusion Parameters in Differentiating from Recurrent/Progressive Tumors?

“…Another factor that can particularly complicate permeability estimates is the fact that upregulation of VEGF, which is known to be 1 of the major factors responsible for increased leakiness of blood vessels in tumors, 28 and is also upregulated in radiation injury. 29 Recent reports suggesting that anti-VEGF therapy can be used in patients with radiation necrosis supports the role played by VEGF signaling cascade in radiation injury. 30,31 Vascular Perfusion Parameters in Differentiating TIN from RPT Blood volume estimates obtained by using MR 8,11,27 or PCT 7 techniques have been previously used with significant success in differentiating the 2 entities.…”

Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications

“…103 Analysis of the promoter regions of the various proteins reveals the presence of one or more putative binding sites for each of these transcription factors ( figure 7). Definitive evidence for involvement of all four factors in transcriptional regulation of proteins involved in cerebral oedema has not been published, but some gaps in knowlegde have been filled in, 104,107 including for Aqp4 (AP-1, Sp-1),104 SUR1 (Sp-1), 9,105,106 prothrombin (Sp-1),107 VEGF (Sp-1, HIF-1, AP-1) [108][109][110][111] and MMP-9 (NF-κB). 60,112 Future research will add new details to the transcriptional program proposed here by identifying other hypoxia or redox-activated transcription factors involved.…”

Pathobiology of radiation myelopathy and strategies to mitigate injury

“…After thoracolumbar radiation in transgenic mice with differential VEGF expression levels, VEGF-low mice were protected from hindlimb paralysis compared with wild-type and VEGH-high mice. 31 Upregulation of intercellular adhesion molecule-1 is associated with a variety of CNS insults with blood-brain barrier disruption. In rat spinal cord, there was parallel temporal and spatial intercellular adhesion molecule-1 upregulation associated with BSCB disruption after radiation.…”