Vascular Cell Senescence Contributes to Blood–Brain Barrier Breakdown

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29 Citations (Scopus)

Abstract

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) 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 mice had increased senescent-associated β-galactosidase activity and p16 expression, demonstrating an exacerbation of senescence. The coverage by tight junction proteins in the cortical microvessels were reduced in BubR1 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 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.

Original languageEnglish (US)
JournalStroke
DOIs
StateAccepted/In press - Feb 16 2016

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Cell Aging
Pericytes
Blood Vessels
Tight Junctions
Microvessels
Endothelial Cells
Astrocytes
Galactosidases
Tight Junction Proteins
Evans Blue
Aquaporins
Fluorescein
Electric Impedance
Albumins
Permeability
Phenotype
In Vitro Techniques

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing

Cite this

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title = "Vascular Cell Senescence Contributes to Blood–Brain Barrier Breakdown",
abstract = "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) 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 mice had increased senescent-associated β-galactosidase activity and p16 expression, demonstrating an exacerbation of senescence. The coverage by tight junction proteins in the cortical microvessels were reduced in BubR1 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 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.",
author = "Y. Yamazaki and Baker, {Darren J} and Masaya Tachibana and Chia-Chen Liu and {Van Deursen}, Jan and Brott, {Thomas G} and Bu, {Guojun D} and Takahisa Kanekiyo",
year = "2016",
month = "2",
day = "16",
doi = "10.1161/STROKEAHA.115.010835",
language = "English (US)",
journal = "Stroke",
issn = "0039-2499",
publisher = "Lippincott Williams and Wilkins",

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T1 - Vascular Cell Senescence Contributes to Blood–Brain Barrier Breakdown

AU - Yamazaki, Y.

AU - Baker, Darren J

AU - Tachibana, Masaya

AU - Liu, Chia-Chen

AU - Van Deursen, Jan

AU - Brott, Thomas G

AU - Bu, Guojun D

AU - Kanekiyo, Takahisa

PY - 2016/2/16

Y1 - 2016/2/16

N2 - 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) 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 mice had increased senescent-associated β-galactosidase activity and p16 expression, demonstrating an exacerbation of senescence. The coverage by tight junction proteins in the cortical microvessels were reduced in BubR1 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 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.

AB - 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) 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 mice had increased senescent-associated β-galactosidase activity and p16 expression, demonstrating an exacerbation of senescence. The coverage by tight junction proteins in the cortical microvessels were reduced in BubR1 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 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.

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