Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown.
BACKGROUND AND PURPOSE
Age-related changes in the cerebrovasculature, including blood-brain barrier (BBB) disruption, are emerging as potential risks for diverse neurological conditions. Because the accumulation of senescent cells in tissues is increasingly recognized as a critical step leading to age-related organ dysfunction, we evaluated whether senescent vascular cells are associated with compromised BBB integrity.


METHODS
Effects of vascular cell senescence on tight junction and barrier integrity were studied using an in vitro BBB model, composed of endothelial cells, pericytes, and astrocytes. In addition, tight junction coverage in microvessels and BBB integrity in BubR1 hypomorphic (BubR1(H/H)) mice, which display senescence cell-dependent phenotypes, were examined.


RESULTS
When an in vitro BBB model was constructed with senescent endothelial cells and pericytes, tight junction structure and barrier integrity (evaluated by transendothelial electric resistance and tracer efflux assay using sodium fluorescein and Evans blue-albumin were significantly impaired. Endothelial cells and pericytes from BubR1(H/H) mice had increased senescent-associated β-galactosidase activity and p16(INK4a) expression, demonstrating an exacerbation of senescence. The coverage by tight junction proteins in the cortical microvessels were reduced in BubR1(H/H) mice, consistent with a compromised BBB integrity from permeability assays. Importantly, the coverage of microvessels by end-feet of aquaporin 4-immunoreactive astrocytes was not altered in the cortex of the BubR1(H/H) mice.


CONCLUSIONS
Our results indicate that accumulation of senescent vascular cells is associated with compromised BBB integrity, providing insights into the mechanism of BBB disruption related to biological aging.
['Yamazaki|Yu|Y|', 'Baker|Darren J|DJ|', 'Tachibana|Masaya|M|', 'Liu|Chia-Chen|CC|', 'van Deursen|Jan M|JM|', 'Brott|Thomas G|TG|', 'Bu|Guojun|G|', 'Kanekiyo|Takahisa|T|']
D000375:Aging D000818:Animals D051401:Aquaporin 4 D001253:Astrocytes D001812:Blood-Brain Barrier D001921:Brain D002199:Capillary Permeability D016922:Cellular Senescence D019941:Cyclin-Dependent Kinase Inhibitor p16 D042783:Endothelial Cells D051379:Mice D020286:Pericytes D019108:Tight Junctions D001616:beta-Galactosidase
tight junctions endothelial cells pericytes permeability aging brain