title: Ultrastructural analysis of blood-brain barrier breakdown in the peri-infarct zone in young adult and aged mice.
abstract: Following ischemia, the blood-brain barrier is compromised in the peri-infarct zone leading to secondary injury and dysfunction that can limit recovery. Currently, it is uncertain what structural changes could account for blood-brain barrier permeability, particularly with aging. Here we examined the ultrastructure of early and delayed changes (3 versus 72 h) to the blood-brain barrier in young adult and aged mice (3-4 versus 18 months) subjected to photothrombotic stroke. At both time points and ages, permeability was associated with a striking increase in endothelial caveolae and vacuoles. Tight junctions were generally intact although small spaces were detected in a few cases. In young mice, ischemia led to a significant increase in pericyte process area and vessel coverage whereas these changes were attenuated with aging. Stroke led to an expansion of the basement membrane region that peaked at 3 h and partially recovered by 72 h in both age groups. Astrocyte endfeet and their mitochondria were severely swollen at both times points and ages. Our results suggest that blood-brain barrier permeability in young and aged animals is mediated by transcellular pathways (caveolae/vacuoles), rather than tight junction loss. Further, our data indicate that the effects of ischemia on pericytes and basement membrane are affected by aging.
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, Canada Department of Biology, University of Victoria, Victoria, Canada Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Nahirney
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, Canada.
authors.forename: Patrick
authors.initials: P
authors.lastname: Reeson
authors.affiliation: Division of Medical Sciences, University of Victoria, Victoria, Canada Department of Biology, University of Victoria, Victoria, Canada Department of Psychiatry, University of British Columbia, Vancouver, Canada brownc@uvic.ca.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Brown
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001485:Basement Membrane / Q000473:pathology; D001812:Blood-Brain Barrier / Q000473:pathology* / Q000648:ultrastructure*; D002545:Brain Ischemia / Q000473:pathology; D021941:Caveolae / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology*; D004730:Endothelium, Vascular / Q000473:pathology; D020767:Intracranial Thrombosis / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000473:pathology; D008933:Mitochondrial Swelling; D020286:Pericytes / Q000473:pathology; D010539:Permeability; D020521:Stroke / Q000473:pathology; D019108:Tight Junctions; D014617:Vacuoles / Q000473:pathology
keywords: Stroke; aging; astrocytes; basement membrane; blood–brain barrier; endothelium; extravasation; ischemia; pericytes; transcytosis