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Nat Commun. 2016 Jan 27;7:10523. doi: 10.1038/ncomms10523.

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

Shi Y1,2, Zhang L1,3,4, Pu H1,3, Mao L1,3, Hu X1,3,4, Jiang X1,3, Xu N3, Stetler RA1,3,4, Zhang F1,3,4, Liu X1,2, Leak RK5, Keep RF6, Ji X2, Chen J1,3,4.

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Center of Cerebrovascular Disease Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
China-America Institute of Neuroscience, Xuanwu Hospital, Capital Medical University, Beijing 100053, China.
State Key Laboratory of Medical Neurobiology, Institute of Brain Science and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai 200032, China.
Geriatric Research, Educational and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania 15261, USA.
Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, Pittsburgh, Pennsylvania 15282, USA.
Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan 48109, USA.


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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