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Cited by 431Barrier Structure and Function StudiesAcute Ischemic Stroke ManagementIntracerebral and Subarachnoid Hemorrhage Research

Rapid endothelial cytoskeletal reorganization enables early blood–brain barrier disruption and long-term ischaemic reperfusion brain injury

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Shi, Yejie, Zhang, Lili, Pu, Hongjian, Mao, Leilei, Hu, Xiaoming, Jiang, Xiaoyan, Xu, Na, Stetler, R. Anne +6 more·2016·Nature Communications
DOI 10.1038/ncomms10523PMC PMC4737895
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Abstract

The mechanism and long-term consequences of early blood–brain barrier (BBB) disruption after cerebral ischaemic/reperfusion (I/R) injury are poorly understood. Here we discover that I/R induces subtle BBB leakage within 30–60 min, likely independent of gelatinase B/MMP-9 activities. The early BBB disruption is caused by the activation of ROCK/MLC signalling, persistent actin polymerization and the disassembly of junctional proteins within microvascular endothelial cells (ECs). Furthermore, the EC alterations facilitate subsequent infiltration of peripheral immune cells, including MMP-9-producing neutrophils/macrophages, resulting in late-onset, irreversible BBB damage. Inactivation of actin depolymerizing factor (ADF) causes sustained actin polymerization in ECs, whereas EC-targeted overexpression of constitutively active mutant ADF reduces actin polymerization and junctional protein disassembly, attenuates both early- and late-onset BBB impairment, and improves long-term histological and neurological outcomes. Thus, we identify a previously unexplored role for early BBB disruption in stroke outcomes, whereby BBB rupture may be a cause rather than a consequence of parenchymal cell injury.

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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 [534]

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Cited by

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Authors
Shi, Y., Zhang, L., Pu, H., Mao, L., Hu, X., Jiang, X., Xu, N., Stetler, R. A., Zhang, F., Liu, X., Leak, R. K., Keep, R. F., Ji, X., & Chen, J.
Affiliations
  • University of Pittsburgh (US)
  • Fudan University (CN)
  • Duquesne University (US)
  • University of Michigan (US)
  • Capital Medical University (CN)
Corresponding author
  • Ji, Xunming
  • Chen, Jun
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-01-27
Volume
7
Issue
1
Pages
10523-10523
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms10523
PMC
PMC4737895
OpenAlex
W2263957136
Cited by
431
References
4
Citations by year
2026: 36 · 2025: 46 · 2024: 39 · 2023: 38 · 2022: 57 · 2021: 61 · 2020: 43 · 2019: 34 · 2018: 45 · 2017: 25 · 2016: 6 · 2015: 1
FWCI
20.09
Type
journal article
Language
en
Update notices
correction (2020-08-25)
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Veterans Affairs (I01 BX002495, BX002495)
  • American Heart Association (15POST22260011)
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (NS-045048, R01NS092810, NS092810, R01NS089534, R01NS056118, R01NS045048, NS089534, NS056118.)
Topics
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
Keywords
blood-brain barrier disruption, stroke, endothelial cytoskeleton, actin polymerization, actin depolymerizing factor, MMP-9, neutrophils, macrophages, immune cell infiltration, microvascular endothelial cells, BBB leakage
MeSH terms
Actins, Animals, Blood-Brain Barrier, Brain Ischemia, Cytoskeleton, Humans, Male, Reperfusion Injury, Matrix Metalloproteinase 9, Endothelial Cells, Mice, Polymerization

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