Rapid endothelial cytoskeletal reorganization enables early blood-brain barrier disruption and long-term ischaemic reperfusion brain injury.
Rapid endothelial cytoskeletal reorganization enables early blood-brain barrier disruption and long-term ischaemic reperfusion brain injury.
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DOI：
10.1038/ncomms10523
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发表时间：
2016-01-27
影响因子：
16.6
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Shi Y;Zhang L;Pu H;Mao L;Hu X;Jiang X;Xu N;Stetler RA;Zhang F;Liu X;Leak RK;Keep RF;Ji X;Chen J
脑缺血/再灌注（I/R）损伤后早期血脑屏障（BBB）破坏的机制和长期后果尚不清楚。我们发现I/R在30-60分钟内诱导轻微的BB B渗漏，可能与明胶酶B/MMP-9活性无关。早期血脑屏障破坏是由ROCK/MLC信号的激活、持续的肌动蛋白聚合和微血管内皮细胞（EC）内连接蛋白的分解引起的。此外，EC改变促进随后的外周免疫细胞（包括产生MMP-9的中性粒细胞/巨噬细胞）的浸润，导致迟发性、不可逆的BBB损伤。肌动蛋白解聚因子（ADF）的失活导致EC中持续的肌动蛋白聚合，而EC靶向的组成型活性突变体ADF的过表达减少了肌动蛋白聚合和连接蛋白分解，减弱了早发性和迟发性BBB损伤，并改善了长期的组织学和神经学结局。因此，我们确定了一个以前未探索的作用，早期血脑屏障破坏中风的结果，血脑屏障破裂可能是一个原因，而不是实质细胞损伤的后果。 从浸润的免疫细胞释放的基质金属蛋白酶（MMPs）是中风后血脑屏障（BBB）破坏的主要贡献者。在这里，作者确定了一个早期的，MMP-独立的血脑屏障破坏机制引起的快速细胞骨架重排的内皮细胞，这可以抑制ADF。
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.