This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, Y.-Q. Articles by Wong, C. S. Search for Related Content PubMed PubMed Citation Articles by Li, Y.-Q. Articles by Wong, C. S.

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.

This article has been cited by other articles:

				Y. Cao, C. I. Tsien, P. C. Sundgren, V. Nagesh, D. Normolle, H. Buchtel, L. Junck, and T. S. Lawrence Dynamic Contrast-Enhanced Magnetic Resonance Imaging As a Biomarker for Prediction of Radiation-Induced Neurocognitive Dysfunction Clin. Cancer Res., March 1, 2009; 15(5): 1747 - 1754. [Abstract] [Full Text] [PDF]

				S. Wang, E. X. Wu, D. Qiu, L. H.T. Leung, H.-F. Lau, and P.-L. Khong Longitudinal Diffusion Tensor Magnetic Resonance Imaging Study of Radiation-Induced White Matter Damage in a Rat Model Cancer Res., February 1, 2009; 69(3): 1190 - 1198. [Abstract] [Full Text] [PDF]

				E. L. Smith and E. H. Schuchman The unexpected role of acid sphingomyelinase in cell death and the pathophysiology of common diseases FASEB J, October 1, 2008; 22(10): 3419 - 3431. [Abstract] [Full Text] [PDF]

				S. Bonnaud, C. Niaudet, G. Pottier, M.-H. Gaugler, J. Millour, J. Barbet, L. Sabatier, and F. Paris Sphingosine-1-Phosphate Protects Proliferating Endothelial Cells from Ceramide-Induced Apoptosis but not from DNA Damage-Induced Mitotic Death Cancer Res., February 15, 2007; 67(4): 1803 - 1811. [Abstract] [Full Text] [PDF]

				J. J. Ohab, S. Fleming, A. Blesch, and S. T. Carmichael A Neurovascular Niche for Neurogenesis after Stroke J. Neurosci., December 13, 2006; 26(50): 13007 - 13016. [Abstract] [Full Text] [PDF]

				E. Gulbins and P. L. Li Physiological and pathophysiological aspects of ceramide Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R11 - R26. [Abstract] [Full Text] [PDF]

				F. Galimi, R. G. Summers, H. van Praag, I. M. Verma, and F. H. Gage A role for bone marrow-derived cells in the vasculature of noninjured CNS Blood, March 15, 2005; 105(6): 2400 - 2402. [Abstract] [Full Text] [PDF]

				J B Reitan, L Brinch, and K Beiske Multi-organ failure aspects of a fatal radiation accident in Norway in 1982 Br. J. Radiol., January 1, 2005; Supplement_27(1): 36 - 40. [Abstract] [Full Text] [PDF]

				M-H Gaugler A unifying system: does the vascular endothelium have a role to play in multi-organ failure following radiation exposure? Br. J. Radiol., January 1, 2005; Supplement 27(1): 100 - 105. [Abstract] [Full Text] [PDF]

				C. S. Wong and A. J. Van der Kogel MECHANISMS OF RADIATION INJURY TO THE CENTRAL NERVOUS SYSTEM: IMPLICATIONS FOR NEUROPROTECTION Mol. Interv., October 1, 2004; 4(5): 273 - 284. [Abstract] [Full Text] [PDF]

				D. S. Gregerson and H. Kawashima APC derived from donor splenocytes support retinal autoimmune disease in allogeneic recipients J. Leukoc. Biol., August 1, 2004; 76(2): 383 - 387. [Abstract] [Full Text] [PDF]