Open AccessRapid endothelial cytoskeletal reorganization enables early blood–brain barrier disruption and long-term ischaemic reperfusion brain injury
Author(s) -
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
Publication year - 2016
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/ncomms10523
Subject(s) - blood–brain barrier , microbiology and biotechnology , cytoskeleton , tight junction , parenchyma , actin cytoskeleton , chemistry , biology , cell , pathology , medicine , central nervous system , neuroscience , biochemistry
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.