Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover.
Akt1 promotes stimuli-induced endothelial-barrier protection through FoxO-mediated tight-junction protein turnover.
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DOI：
10.1007/s00018-016-2232-z
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发表时间：
2016-10
影响因子：
8
通讯作者：
Somanath, Payaningal R.
中科院分区：
文献类型：
--
作者：
Gao, Fei;Artham, Sandeep;Sabbineni, Harika;Al-Azayzih, Ahmad;Peng, Xiao-Ding;Hay, Nissim;Adams, Ralf H.;Byzova, Tatiana V.;Somanath, Payaningal R.
血管内皮生长因子（VEGF）通过内皮-屏障连接调节血管通透性是炎症的关键。调节血管通透性的机制仍然是难以捉摸的。虽然'Akt'和'Src'已被牵连在内皮屏障的调节，这是令人费解的是如何保护和破坏内皮屏障的代理激活这些激酶，以间接调节血管通透性。为了描述Akt 1在内皮屏障调节中的作用，我们建立了内皮特异性的、他莫昔芬诱导的Akt 1敲除小鼠和稳定的ShRNA介导的人微血管内皮细胞中的Akt 1敲除。Akt 1缺失导致基础和血管生成素1诱导的内皮屏障阻力降低，并增强VEGF诱导的内皮屏障破坏。内皮细胞Akt 1缺陷导致VEGF诱导的小鼠耳血管渗漏增强，这在Adeno-myrAkt 1重新表达后得到挽救。此外，与血管生成素1的共同治疗逆转VEGF诱导的血管渗漏在Akt 1依赖性的方式。从机制上讲，我们的研究表明，虽然VEGF诱导的短期血管通透性是独立的Akt 1，其恢复依赖于Akt 1和FoxO介导的claudin表达。FoxO转录因子的药理学抑制挽救了由于Akt 1缺陷而导致的有缺陷的内皮屏障。在这里，我们提供了新的见解血管内皮生长因子在长期的内皮屏障保护作用和Akt 1-FoxO信号对紧密连接的稳定和预防血管渗漏通过claudin表达的重要性。
Vascular permeability regulated by the vascular endothelial growth factor (VEGF) through endothelial-barrier junctions is essential for inflammation. Mechanisms regulating vascular permeability remain elusive. Although ‘Akt’ and ‘Src’ have been implicated in the endothelial-barrier regulation, it is puzzling how both agents that protect and disrupt the endothelial-barrier activate these kinases to reciprocally regulate vascular permeability. To delineate the role of Akt1 in endothelial-barrier regulation, we created endothelial-specific, tamoxifen-inducible Akt1 knockout mice and stable ShRNA-mediated Akt1 knockdown in human microvascular endothelial cells. Akt1 loss leads to decreased basal and angiopoietin1-induced endothelial-barrier resistance, and enhanced VEGF-induced endothelial-barrier breakdown. Endothelial Akt1 deficiency resulted in enhanced VEGF-induced vascular leakage in mice ears, which was rescued upon re-expression with Adeno-myrAkt1. Furthermore, co-treatment with angiopoietin1 reversed VEGF-induced vascular leakage in an Akt1-dependent manner. Mechanistically, our study revealed that while VEGF-induced short-term vascular permeability is independent of Akt1, its recovery is reliant on Akt1 and FoxO-mediated claudin expression. Pharmacological inhibition of FoxO transcription factors rescued the defective endothelial-barrier due to Akt1 deficiency. Here we provide novel insights on the endothelial-barrier protective role of VEGF in the long-term and the importance of Akt1-FoxO signaling on tight-junction stabilization and prevention of vascular leakage through claudin expression.
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影响因子：
6.7
作者：
Goddard LM;Iruela-Arispe ML
通讯作者：
Iruela-Arispe ML
影响因子：
82.9
作者：
Chen, JH;Somanath, PR;Byzova, TV
通讯作者：
Byzova, TV
影响因子：
4.8
作者：
Goc, Anna;Al-Azayzih, Ahmad;Somanath, Payaningal R.
通讯作者：
Somanath, Payaningal R.
影响因子：
7.8
作者：
Ngok, Siu P.;Geyer, Rory;Anastasiadis, Panos Z.
通讯作者：
Anastasiadis, Panos Z.
影响因子：
15.9
作者：
Murakami, Masahiro;Nguyen, Loc T.;Simons, Michael
通讯作者：
Simons, Michael