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Endothelial Apoptosis Initiates Acute Blood–Brain Barrier Disruption after Ionizing Radiation¹

Department of Radiation Oncology, Sunnybrook and Women’s College Health Sciences Center, University of Toronto, Toronto, Ontario, M4N 3M5 Canada [Y-Q. L., C. S. W.]; Division of Nuclear Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, M5G 2C4 Canada [P. C., R. M. R.]; and Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [A. H-F.]

Acute disruption of blood–brain barrier (BBB) is well recognized after radiation therapy to the central nervous system (CNS). We assessed the genetic regulation of acute BBB disruption and its relationship to vascular endothelial cell death in the CNS after irradiation. Adult rats were given graded single doses of X-ray to the cervical spinal cord. At different time intervals after irradiation, the irradiated spinal cord was processed for histological and immunohistochemical analysis. Disruption of blood–spinal cord barrier was assessed using albumin immunohistochemistry, i.v. injection of Evans blue dye, and ^99mTc-diethylenetriamine pentaacetic acid. In the rat spinal cord, there was a dose-dependent apoptotic response during the first 24 h after irradiation, and apoptotic cells consisted of both endothelial and glial cells, as described previously (1 , 2) . A dose-dependent reduction in endothelial cell density was observed at 24 h after irradiation. This was associated with a similar dose-dependent disruption in blood–spinal cord barrier as demonstrated by albumin immunohistochemistry. Radiation-induced apoptosis in endothelial cells has been shown to be dependent on the acid sphingomyelinase (ASMase) pathway. After a single 50-Gy dose to the cervical spinal cord of ASMase +/+ mice, there was a 47.7% reduction in endothelial cell density at 24 h compared with nonirradiated controls. No decrease in endothelial cell density was observed in irradiated ASMase -/- mice. In the irradiated spinal cord of ASMase +/+ mice, there was evidence of albumin immunoreactivity and Evans blue dye staining around microvessels, and ^99mTc-diethylenetriamine pentaacetic acid uptake increased at 24 h. Nonirradiated controls and the irradiated spinal cord of ASMase -/- mice demonstrated no evidence of leakage. We conclude that apoptosis of endothelial cells initiates acute BBB disruption in the CNS after irradiation and that acute BBB disruption after irradiation is mediated by the ASMase pathway.

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