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Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown.
Stroke 2016; 47(4):1068-77S

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(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.

Authors+Show Affiliations

From the Departments of Neuroscience (Y.Y., M.T., C-C.L., G.B., T.K.) and Neurology (T.G.B.), Mayo Clinic, Jacksonville, FL; and Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN (D.J.B., J.M.v.D.).From the Departments of Neuroscience (Y.Y., M.T., C-C.L., G.B., T.K.) and Neurology (T.G.B.), Mayo Clinic, Jacksonville, FL; and Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN (D.J.B., J.M.v.D.).From the Departments of Neuroscience (Y.Y., M.T., C-C.L., G.B., T.K.) and Neurology (T.G.B.), Mayo Clinic, Jacksonville, FL; and Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN (D.J.B., J.M.v.D.).From the Departments of Neuroscience (Y.Y., M.T., C-C.L., G.B., T.K.) and Neurology (T.G.B.), Mayo Clinic, Jacksonville, FL; and Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN (D.J.B., J.M.v.D.).From the Departments of Neuroscience (Y.Y., M.T., C-C.L., G.B., T.K.) and Neurology (T.G.B.), Mayo Clinic, Jacksonville, FL; and Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN (D.J.B., J.M.v.D.).From the Departments of Neuroscience (Y.Y., M.T., C-C.L., G.B., T.K.) and Neurology (T.G.B.), Mayo Clinic, Jacksonville, FL; and Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN (D.J.B., J.M.v.D.).From the Departments of Neuroscience (Y.Y., M.T., C-C.L., G.B., T.K.) and Neurology (T.G.B.), Mayo Clinic, Jacksonville, FL; and Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN (D.J.B., J.M.v.D.).From the Departments of Neuroscience (Y.Y., M.T., C-C.L., G.B., T.K.) and Neurology (T.G.B.), Mayo Clinic, Jacksonville, FL; and Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN (D.J.B., J.M.v.D.). kanekiyo.takahisa@mayo.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26883501

Citation

Yamazaki, Yu, et al. "Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown." Stroke, vol. 47, no. 4, 2016, pp. 1068-77.
Yamazaki Y, Baker DJ, Tachibana M, et al. Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown. Stroke. 2016;47(4):1068-77.
Yamazaki, Y., Baker, D. J., Tachibana, M., Liu, C. C., van Deursen, J. M., Brott, T. G., ... Kanekiyo, T. (2016). Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown. Stroke, 47(4), pp. 1068-77. doi:10.1161/STROKEAHA.115.010835.
Yamazaki Y, et al. Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown. Stroke. 2016;47(4):1068-77. PubMed PMID: 26883501.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vascular Cell Senescence Contributes to Blood-Brain Barrier Breakdown. AU - Yamazaki,Yu, AU - Baker,Darren J, AU - Tachibana,Masaya, AU - Liu,Chia-Chen, AU - van Deursen,Jan M, AU - Brott,Thomas G, AU - Bu,Guojun, AU - Kanekiyo,Takahisa, Y1 - 2016/02/16/ PY - 2015/07/14/received PY - 2016/01/26/accepted PY - 2016/2/18/entrez PY - 2016/2/18/pubmed PY - 2016/9/10/medline KW - aging KW - brain KW - endothelial cells KW - pericytes KW - permeability KW - tight junctions SP - 1068 EP - 77 JF - Stroke JO - Stroke VL - 47 IS - 4 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(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. SN - 1524-4628 UR - https://www.unboundmedicine.com/medline/citation/26883501/Vascular_Cell_Senescence_Contributes_to_Blood_Brain_Barrier_Breakdown_ L2 - http://www.ahajournals.org/doi/full/10.1161/STROKEAHA.115.010835?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -