Annexin A2 is a Robo4 ligand that modulates ARF6 activation-associated cerebral trans-endothelial permeability
Annexin A2 is a Robo4 ligand that modulates ARF6 activation-associated cerebral trans-endothelial permeability
复制标题
annexin A2 是 Robo4 配体，可调节 ARF6 激活相关的大脑跨内皮通透性。
DOI：
10.1177/0271678x18777916
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发表时间：
2019-10-01
影响因子：
6.3
通讯作者：
Wang, Xiaoying
中科院分区：
文献类型：
--
作者：
Li, Wenlu;Chen, Zhigang;Wang, Xiaoying
神经系统疾病中的血脑屏障（BBB）破坏仍然是一个棘手的问题，治疗选择有限。在这里，我们调查是否内皮细胞膜蛋白膜联蛋白A2（ANXA 2）可能发挥作用，在减少跨内皮通透性和维持脑血管损伤后的完整性。与野生型小鼠相比，E15.5和成年ANXA 2基因敲除小鼠脑内皮连接蛋白的表达减少，沿着小分子示踪剂的泄漏增加。在缺氧加IL-1 β损伤的人脑内皮细胞中，用重组ANXA 2（rA 2）治疗挽救了连接蛋白的表达并降低了跨内皮渗透性。这些保护作用部分由与F-肌动蛋白和VE-钙粘蛋白的相互作用以及rA 2通过迂回引导受体4（Robo 4）-paxillin-ADP-核糖基化因子6（ARF 6）途径调节信号传导的能力介导。总之，这些观察结果表明，ANXA 2可能与脑血管损伤后内皮紧密性的维持有关。ANXA 2介导的通路应进一步探索作为保护神经系统疾病中BBB的潜在治疗靶点。
Blood-brain barrier (BBB) disruption in neurological disorders remains an intractable problem with limited therapeutic options. Here, we investigate whether the endothelial cell membrane protein annexin A2 (ANXA2) may play a role in reducing trans-endothelial permeability and maintaining cerebrovascular integrity after injury. Compared with wild-type mice, the expression of cerebral endothelial junctional proteins was reduced in E15.5 and adult ANXA2 knockout mice, along with increased leakage of small molecule tracers. In human brain endothelial cells that were damaged by hypoxia plus IL-1 beta, treatment with recombinant ANXA2 (rA2) rescued the expression of junctional proteins and decreased trans-endothelial permeability. These protective effects were mediated in part by interactions with F-actin and VE-cadherin, and the ability of rA2 to modulate signaling via the roundabout guidance receptor 4 (Robo4)-paxillin-ADP-ribosylation factor 6 (ARF6) pathway. Taken together, these observations suggest that ANXA2 may be associated with the maintenance of endothelial tightness after cerebrovascular injury. ANXA2-mediated pathways should be further explored as potential therapeutic targets for protecting the BBB in neurological disorders.