Department of Pharmacology, University of Illinois, 835 S Wolcott, Room E403, Mail code 868, Chicago, IL 60612, USA.
Circ Res. 2010 Oct 15;107(8):959-66. doi: 10.1161/CIRCRESAHA.110.219592. Epub 2010 Aug 19.
Vascular endothelial (VE)-cadherin localized at adherens junctions (AJs) regulates endothelial barrier function. Because WNT (wingless) signaling-induced activation of the transcription factor Krüppel-like factor (KLF)4 may have an important role in mediating the expression of VE-cadherin and AJ integrity, we studied the function of KLF4 in regulating VE-cadherin expression and the control of endothelial barrier function.
The goal of this study was to determine the transcriptional role of KLF4 in regulating VE-cadherin expression and endothelial barrier function.
Expression analysis, microscopy, chromatin immunoprecipitation, electrophoretic mobility shift assays, and VE-cadherin-luciferase reporter experiments demonstrated that KLF4 interacted with specific domains of VE-cadherin promoter and regulated the expression of VE-cadherin at AJs. KLF4 knockdown disrupted the endothelial barrier, indicating that KLF4 is required for normal barrier function. In vivo studies in mice showed augmented lipopolysaccharide-induced lung injury and pulmonary edema following Klf4 depletion.
Our data show the key role of KLF4 in the regulation of VE-cadherin expression at the level of the AJs and in the acquisition of VE-cadherin-mediated endothelial barrier function. Thus, KLF4 maintains the integrity of AJs and prevents vascular leakage in response to inflammatory stimuli.
血管内皮（VE）-钙黏蛋白定位于黏附连接（AJ）处，调节内皮屏障功能。因为 WNT（无翅型）信号诱导的转录因子 Krüppel 样因子（KLF）4 的激活可能在介导 VE-钙黏蛋白的表达和 AJ 完整性中具有重要作用，所以我们研究了 KLF4 在调节 VE-钙黏蛋白表达和控制内皮屏障功能中的作用。
本研究的目的是确定 KLF4 在调节 VE-钙黏蛋白表达和内皮屏障功能中的转录作用。
表达分析、显微镜检查、染色质免疫沉淀、电泳迁移率变动分析和 VE-钙黏蛋白荧光素酶报告实验表明，KLF4 与 VE-钙黏蛋白启动子的特定区域相互作用，并调节 AJ 处的 VE-钙黏蛋白表达。KLF4 敲低破坏了内皮屏障，表明 KLF4 是正常屏障功能所必需的。在小鼠体内研究中，Klf4 耗竭后，脂多糖诱导的肺损伤和肺水肿加剧。
我们的数据表明 KLF4 在 AJ 水平上调节 VE-钙黏蛋白表达和获得 VE-钙黏蛋白介导的内皮屏障功能方面发挥着关键作用。因此，KLF4 维持 AJ 的完整性，并防止血管在炎症刺激下渗漏。
