Effects of fractionated radiation on the brain vasculature in a murine model: blood-brain barrier permeability, astrocyte proliferation, and ultrastructural changes.
OBJECTIVE
Radiation therapy of CNS tumors damages the blood-brain barrier (BBB) and normal brain tissue. Our aims were to characterize the short- and long-term effects of fractionated radiotherapy (FRT) on cerebral microvasculature in mice and to investigate the mechanism of change in BBB permeability in mice.


METHODS
Intravital microscopy and a cranial window technique were used to measure BBB permeability to fluorescein isothiocyanate (FITC)-dextran and leukocyte endothelial interactions before and after cranial irradiation. Daily doses of 2 Gy were delivered 5 days/week (total, 40 Gy). We immunostained the molecules to detect the expression of glial fibrillary acidic protein and to demonstrate astrocyte activity in brain parenchyma. To relate the permeability changes to endothelial ultrastructural changes, we used electron microscopy.


RESULTS
Blood-brain barrier permeability did not increase significantly until 90 days after FRT, at which point it increased continuously until 180 days post-FRT. The number of adherent leukocytes did not increase during the study. The number of astrocytes in the cerebral cortex increased significantly; vesicular activity in endothelial cells increased beginning 90 days after irradiation, and most tight junctions stayed intact, although some were shorter and less dense at 120 and 180 days.


CONCLUSIONS
The cellular and microvasculature response of the brain to FRT is mediated through astrogliosis and ultrastructural changes, accompanied by an increase in BBB permeability. The response to FRT is delayed as compared with single-dose irradiation treatment, and does not involve leukocyte adhesion. However, FRT induces an increase in the BBB permeability, as in the case of single-dose irradiation.
Yuan
Hong
H
Department of BioImaging, College of Health Science Engineering, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Gaber
M Waleed
MW
Boyd
Kelli
K
Wilson
Christy M
CM
Kiani
Mohammad F
MF
Merchant
Thomas E
TE
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000528:radiation effects*; D001812:Blood-Brain Barrier / Q000528:radiation effects*; D001921:Brain / Q000098:blood supply* / Q000166:cytology / Q000648:ultrastructure; D002199:Capillary Permeability; D002448:Cell Adhesion; D002455:Cell Division / Q000528:radiation effects; D002560:Cerebrovascular Circulation; D016371:Cranial Irradiation; D042783:Endothelial Cells / Q000166:cytology / Q000528:radiation effects; D016650:Fluorescein-5-isothiocyanate / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000528:radiation effects
D005456:Fluorescent Dyes; D016650:Fluorescein-5-isothiocyanate