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

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 () and Jun Chen ()
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Yejie Shi: Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
Lili Zhang: Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
Hongjian Pu: Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
Leilei Mao: Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
Xiaoming Hu: Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
Xiaoyan Jiang: Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
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
Feng Zhang: Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
Xiangrong Liu: Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine
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

Nature Communications, 2016, vol. 7, issue 1, 1-18

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10523

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