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

• Published in: Nature communications Vol. 7; no. 1; p. 10523
• Main Authors: Shi, Yejie, Zhang, Lili, Pu, Hongjian, Mao, Leilei, Hu, Xiaoming, Jiang, Xiaoyan, Xu, Na, Stetler, R. Anne, Zhang, Feng, Liu, Xiangrong, Leak, Rehana K., Keep, Richard F., Ji, Xunming, Chen, Jun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.01.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 13/31; 13/51; 631/378/1341; 631/378/1689/534; 631/80/128; 64/60; 692/699/375/1345; Actin; Actins - chemistry; Actins - metabolism; Animals; Blood-brain barrier; Blood-Brain Barrier - metabolism; Brain injury; Brain Ischemia - genetics; Brain Ischemia - metabolism; Breakdown; Cell injury; Cytoskeleton; Cytoskeleton - genetics; Cytoskeleton - metabolism; Deactivation; Depolymerization; Dismantling; Disruption; Endothelial cells; Endothelial Cells - metabolism; Gelatinase; Gelatinase B; Head injuries; Humanities and Social Sciences; Humans; Immune system; Inactivation; Leukocytes (neutrophilic); Macrophages; Male; Matrix metalloproteinase; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Matrix metalloproteinases; Mice; Microvasculature; multidisciplinary; Polymerization; Proteins; Reperfusion; Reperfusion Injury - genetics; Reperfusion Injury - metabolism; Science; Stroke
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10523

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. Matrix metalloproteinases (MMPs) released from infiltrating immune cells are a major contributor to blood-brain barrier (BBB) breakdown following stroke. Here, the authors identify an early, MMP-independent BBB breakdown mechanism caused by rapid cytoskeletal rearrangements in endothelial cells, which could be inhibited by ADF.