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

Author

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  • Yejie Shi

    (Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
    China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University)

  • Lili Zhang

    (Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
    State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University
    Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System)

  • Hongjian Pu

    (Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
    State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University)

  • Leilei Mao

    (Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
    State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University)

  • Xiaoming Hu

    (Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
    State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University
    Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System)

  • Xiaoyan Jiang

    (Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
    State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University)

  • Na Xu

    (State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University)

  • R. Anne Stetler

    (Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
    State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University
    Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System)

  • Feng Zhang

    (Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
    State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University
    Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System)

  • Xiangrong Liu

    (Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
    China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University)

  • Rehana K. Leak

    (Mylan School of Pharmacy, Duquesne University)

  • Richard F. Keep

    (University of Michigan)

  • Xunming Ji

    (China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University)

  • Jun Chen

    (Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
    State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University
    Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System)

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.

Suggested Citation

  • Yejie Shi & Lili Zhang & Hongjian Pu & Leilei Mao & Xiaoming Hu & Xiaoyan Jiang & Na Xu & R. Anne Stetler & Feng Zhang & Xiangrong Liu & Rehana K. Leak & Richard F. Keep & Xunming Ji & Jun Chen, 2016. "Rapid endothelial cytoskeletal reorganization enables early blood–brain barrier disruption and long-term ischaemic reperfusion brain injury," Nature Communications, Nature, vol. 7(1), pages 1-18, April.
  • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10523
    DOI: 10.1038/ncomms10523
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    Cited by:

    1. Mengyan Hu & Tiemei Li & Xiaomeng Ma & Sanxin Liu & Chunyi Li & Zhenchao Huang & Yinyao Lin & Ruizhen Wu & Shisi Wang & Danli Lu & Tingting Lu & Xuejiao Men & Shishi Shen & Huipeng Huang & Yuxin Liu &, 2023. "Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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