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首页> 外文期刊>Journal of Cellular Physiology >Hypoxia selectively disrupts brain microvascular endothelial tight junction complexes through a hypoxia-inducible factor-1 (HIF-1) dependent mechanism
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Hypoxia selectively disrupts brain microvascular endothelial tight junction complexes through a hypoxia-inducible factor-1 (HIF-1) dependent mechanism

机译：缺氧有选择性地破坏大脑微血管通过一个内皮细胞紧密连接复合体低氧诱导因子- 1 (HIF-1)的依赖机制

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摘要

The blood-brain barrier (BBB) constitutes a critical barrier for the maintenance of central nervous system homeostasis. Brain microvascular endothelial cells line the vessel walls and express tight junction (TJ) complexes that restrict paracellular passage across the BBB, thereby fulfilling a crucial role in ensuring brain function. Hypoxia, an impaired O2 delivery, is known to cause BBB dysfunction but the mechanisms that drive this disruption remain unclear. This study discloses the relevance of the master regulator of the hypoxic response, hypoxia-inducible factor-1 (HIF-1), in hypoxia-induced barrier disruption using the rat brain endothelial cell line RBE4. Hypoxic exposure rapidly induced stabilization of the HIF-1 oxygen-dependent alpha subunit (HIF-1α) concomitantly with BBB impairment and TJ disruption mainly through delocalization and increased tyrosine phosphorylation of TJ proteins. Similar observations were obtained by normoxic stabilization of HIF-1α using CoCl2, deferoxamine, and dimethyloxalylglycine underlining the involvement of HIF-1 in barrier dysfunction particularly via TJ alterations. In agreement inhibition of HIF-1 stabilization by 2-methoxyestradiol and YC-1 improved barrier function in hypoxic cells. Overall our data suggests that activation of HIF-1-mediated signaling disrupts TJ resulting in increased BBB permeability.
机译：血脑屏障(BBB)构成维护中央的关键障碍神经系统内稳态。内皮细胞在血管壁和表达紧密连接(TJ)复合物限制paracellular通道在BBB,从而实现在确保一个至关重要的作用大脑功能。导致BBB障碍但这一中断机制仍然存在不清楚。主调节器的缺氧反应,低氧诱导因子- 1 (HIF-1)使用大鼠低氧诱导屏障破坏RBE4大脑内皮细胞线。接触迅速诱导稳定的HIF-1氧依赖性的α亚基(HIF-1α)与此同时BBB障碍和TJ主要通过移位和破坏增加TJ的酪氨酸磷酸化蛋白质。常氧稳定HIF-1使用CoCl2α,去铁胺,dimethyloxalylglycine突显出HIF-1参与的障碍功能障碍尤其是通过TJ改变。协议HIF-1稳定的抑制2-methoxyestradiol和YC-1改善屏障在缺氧细胞功能。表明HIF-1-mediated激活信号干扰TJ导致BBB增加渗透率。

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