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Hypoxia in Radiation-induced Blood-Spinal Cord Barrier Breakdown¹

Division of Experimental Therapeutics [Y-Q. L., J. R. B., R. A. N., C. S. W.] and Department of Radiation Oncology [C. S. W.], Princess Margaret Hospital, and Department of Nuclear Medicine, University Health Network [J. R. B., Z-F. S.], University of Toronto, Toronto, Ontario M5G 2M9, Canada

The vascular endothelial cell is believed to be a major target cell of radiation-induced injury to the central nervous system. Dysfunction of the blood-brain barrier is associated with radiation-induced white matter lesions. The aim of this study was to determine the role of hypoxia in radiation-induced blood-brain barrier disruption. Adult rats were irradiated with graded single doses of 0–22 Gy to the cervical spinal cord. At various times up to 28 weeks after radiation, blood-spinal cord barrier (BSCB) permeability was assessed using immunohistochemistry with antialbumin antibody and gamma counting of ^99mTc-diethylenetriamine pentaacetic acid. Expression of vascular endothelial growth factor (VEGF) was assessed using immunohistochemistry and in situ hybridization. Hypoxia was assessed using two 2-nitroimidazole markers, [¹²⁵I]iodoazomycin arabinodise and 2-(2-nitro-1H-imidazol-l-yl)-N-(2,2,3,3,3,-pentafluoropropyl) acetamide (EF5), with binding in the rat spinal cord measured using gamma counting and immunohistochemistry, respectively. In the nonirradiated rat spinal cord, there was no evidence of BSCB disruption or VEGF expression. After 16–22 Gy, there was a dose-dependent increase in albumin staining and ^99mTc-diethylenetriamine pentaacetic acid activity beginning at 16 weeks, consistent with barrier breakdown. A similar dose-dependent increase in white matter astrocytes that showed immunoreactivity and in situ hybridization signals for VEGF was observed. No increase in VEGF-positive cells was observed in gray matter. By 20 weeks after 20–22 Gy, animals developed white matter necrosis associated with diffuse albumin staining. Irradiated rat spinal cord showed a dose (16–22 Gy)- and time-dependent (16–20 weeks after 22 Gy) increase in [¹²⁵I]iodoazomycin arabinodise accumulation compared to nonirradiated controls. A similar pattern of dose- and time-dependent EF5 immunoreactivity was also observed in white matter. Areas of EF5 expression and VEGF in situ signals colocalized with areas of albumin immunoreactivity. It is concluded that there is a dose-dependent temporal and spatial association of hypoxia, VEGF up-regulation, and radiation-induced BSCB dysfunction. Hypoxia may provide the signal for VEGF up-regulation and perpetuate endothelial permeability damage in the central nervous system after ionizing radiation.

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