Stepwise Recruitment of Transcellular and Paracellular Pathways Underlies Blood-Brain Barrier Breakdown in Stroke
Open accessAbstract
Brain endothelial cells form a paracellular and transcellular barrier to many blood-borne solutes via tight junctions (TJs) and scarce endocytotic vesicles. The blood-brain barrier (BBB) plays a pivotal role in the healthy and diseased CNS. BBB damage after ischemic stroke contributes to increased mortality, yet the contributions of paracellular and transcellular mechanisms to this process in vivo are unknown. We have created a transgenic mouse strain whose endothelial TJs are labeled with eGFP and have imaged dynamic TJ changes and fluorescent tracer leakage across the BBB in vivo, using two-photon microscopy in the t-MCAO stroke model. Although barrier function is impaired as early as 6 hr after stroke, TJs display profound structural defects only after 2 days. Conversely, the number of endothelial caveolae and transcytosis rate increase as early as 6 hr after stroke. Therefore, stepwise impairment of transcellular followed by paracellular barrier mechanisms accounts for the BBB deficits in stroke.
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The first phase of blood-brain barrier opening after ischemia/reperfusion is controlled by subtle endothelial cytoskeleton alterations 30-60 min after injury, followed later by enzymatic cleavage of tight junction proteins after inflammatory cell recruitment.
“The first phase is controlled by subtle endothelial cytoskeleton alterations 30-60 min after ischemia/reperfusion injury, followed later by enzymatic cleavage of TJ proteins after inflammatory cell recruitment (324, 534, 703).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [324]
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- Authors
- Knowland, D., Arac, A., Sekiguchi, K. J., Hsu, M., Lutz, S. E., Perrino, J., Steinberg, G. K., Barres, B. A., Nimmerjahn, A., & Agalliu, D.
- Affiliations
- University of California, Irvine (US)
- Salk Institute for Biological Studies (US)
- Stanford Medicine (US)
- Corresponding author
- Nimmerjahn, Axel
- Agalliu, Dritan
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-05
- Volume
- 82
- Issue
- 3
- Pages
- 603-617
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4016169
- OpenAlex
- W1967076681
- Cited by
- 703
- References
- 8
- Citations by year
- 2026: 53 · 2025: 71 · 2024: 88 · 2023: 67 · 2022: 72 · 2021: 74 · 2020: 63 · 2019: 45 · 2018: 59 · 2017: 46 · 2016: 30 · 2015: 24 · 2014: 11
- FWCI
- 19.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Multiple Sclerosis Society
- Hearst Foundations
- American Heart Association
- Rita Allen Foundation
- Allen Foundation
- National Institutes of Health
- School of Medicine, Stanford University
- National Heart, Lung, and Blood Institute (R01HL116995)
- National Cancer Institute (P30CA014195)
- National Institute of Neurological Disorders and Stroke (1P01 NS37520-08, DP2NS083038, P01NS037520)
- National Center for Chronic Disease Prevention and Health Promotion (1DP2NS083038)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Keywords
- blood-brain barrier disruption, ischemic stroke, tight junctions, paracellular permeability, transcellular permeability, transcytosis, brain endothelial cells, transgenic mouse model, two-photon microscopy
- MeSH terms
- Animals, Blood-Brain Barrier, Male, Mice, Inbred C57BL, Mice, Transgenic, Tight Junctions, Stroke, Endothelial Cells, Mice, Transcytosis
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