FoxM1 regulates re-annealing of endothelial adherens junctions through transcriptional control of beta-catenin expression.
FoxM1 regulates re-annealing of endothelial adherens junctions through transcriptional control of beta-catenin expression.
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DOI：
10.1084/jem.20091857
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发表时间：
2010-08-02
期刊：
影响因子：
--
通讯作者：
Zhao YY
中科院分区：
文献类型：
--
作者：
Mirza MK;Sun Y;Zhao YD;Potula HH;Frey RS;Vogel SM;Malik AB;Zhao YY
损伤血管内膜的修复需要一系列协调事件，介导内皮再生和粘附连接（AJs）的再退火，以形成限制性内皮屏障。叉头转录因子FoxM 1对血管损伤后内皮细胞增殖至关重要。然而，FoxM 1调节内皮屏障再退火的机制知之甚少。在这里，使用小鼠模型与内皮细胞（EC）限制性破坏FoxM 1（FoxM 1 CKO）和原代培养的EC与小干扰RNA（siRNA）介导的FoxM 1敲低，我们证明了一个新的必要的作用，FoxM 1在介导内皮AJ屏障修复通过β-连环蛋白的转录控制。在FoxM 1 CKO肺血管系统中，我们观察到持续的微血管渗漏，其特征在于内皮损伤后内皮AJs的再退火受损。我们还发现，FoxM 1直接调节β-catenin的转录，β-catenin的再表达挽救了FoxM 1缺陷EC的缺陷AJ屏障再退火表型。β-连环蛋白的敲低模拟了FoxM 1缺陷EC中观察到的屏障恢复缺陷的表型。这些数据表明，FoxM 1是内皮AJs再退火所必需的，以便通过β-连环蛋白表达的转录控制形成限制性内皮屏障。因此，激活FoxM 1介导的内皮修复的方法代表了治疗与持续性血管屏障渗漏相关的炎性血管疾病如急性肺损伤的新治疗策略。
Repair of the injured vascular intima requires a series of coordinated events that mediate both endothelial regeneration and reannealing of adherens junctions (AJs) to form a restrictive endothelial barrier. The forkhead transcription factor FoxM1 is essential for endothelial proliferation after vascular injury. However, little is known about mechanisms by which FoxM1 regulates endothelial barrier reannealing. Here, using a mouse model with endothelial cell (EC)-restricted disruption of FoxM1 (FoxM1 CKO) and primary cultures of ECs with small interfering RNA (siRNA)-mediated knockdown of FoxM1, we demonstrate a novel requisite role of FoxM1 in mediating endothelial AJ barrier repair through the transcriptional control of β-catenin. In the FoxM1 CKO lung vasculature, we observed persistent microvessel leakage characterized by impaired reannealing of endothelial AJs after endothelial injury. We also showed that FoxM1 directly regulated β-catenin transcription and that reexpression of β-catenin rescued the defective AJ barrier–reannealing phenotype of FoxM1-deficient ECs. Knockdown of β-catenin mimicked the phenotype of defective barrier recovery seen in FoxM1-deficient ECs. These data demonstrate that FoxM1 is required for reannealing of endothelial AJs in order to form a restrictive endothelial barrier through transcriptional control of β-catenin expression. Therefore, means of activating FoxM1-mediated endothelial repair represent a new therapeutic strategy for the treatment of inflammatory vascular diseases associated with persistent vascular barrier leakiness such as acute lung injury.
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影响因子：
4
作者：
Dejana, Elisabetta;Orsenigo, Fabrizio;Lampugnani, Maria Grazia
通讯作者：
Lampugnani, Maria Grazia
影响因子：
21.3
作者：
Laoukili, J;Kooistra, MRH;Medema, RH
通讯作者：
Medema, RH
影响因子：
9.2
作者：
Korver, W;Schilham, MW;Clevers, H
通讯作者：
Clevers, H
影响因子：
7.5
作者：
Lampugnani, Maria Grazia;Dejanaa, Etisabetta
通讯作者：
Dejanaa, Etisabetta
影响因子：
20.1
作者：
Tiruppathi, C;Freichel, M;Malik, AB
通讯作者：
Malik, AB