Hemodynamic activation of beta-catenin and T-cell-specific transcription factor signaling in vascular endothelium regulates fibronectin expression.
Hemodynamic activation of beta-catenin and T-cell-specific transcription factor signaling in vascular endothelium regulates fibronectin expression.
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DOI：
10.1161/atvbaha.111.227827
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发表时间：
2011-07
期刊：
影响因子：
--
通讯作者：
Blackman BR
中科院分区：
文献类型：
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作者：
Gelfand BD;Meller J;Pryor AW;Kahn M;Bortz PD;Wamhoff BR;Blackman BR
β-连环蛋白/TCF信号传导调节各种细胞功能，包括发育和重塑。纤连蛋白是一种TCF调节基因，在动脉粥样硬化发展过程中在动脉内皮细胞中高度表达，并参与疾病的病理生理过程。然而，内皮β-catenin/TCF信号的激活及其在动脉粥样硬化中纤连蛋白表达中的作用目前尚不清楚。目的探讨β-catenin/TCF信号通路在动脉粥样硬化形成中的作用及其对血管内皮纤维连接蛋白的调节作用。组织学染色鉴定出在病变发展之前和期间，β-连环蛋白在动脉粥样硬化主动脉内皮中的优先核定位。转基因报告基因研究显示，内皮细胞中TCF转录活性水平的增加与β-连环蛋白核定位和纤连蛋白沉积在解剖学上相关。内皮细胞暴露于人源性动脉粥样硬化酮剪切应力诱导β-连环蛋白的核定位、TCF的转录激活和纤连蛋白的表达。纤连蛋白表达的激活需要β-连环蛋白、TCF和转录共激活因子CBP。最后，我们确定PECAM-1是组成性β-catenin和GSK-3β活性的关键调节因子。该数据揭示了动脉粥样硬化中内皮β-连环蛋白/TCF信号通路的新型组成性激活以及通过血流动力学剪切应力调节纤连蛋白。
β-catenin/TCF signaling regulates a varied set of cellular functions including development and remodeling. Fibronectin is a TCF-regulated gene that is highly expressed in arterial endothelium during atherosclerosis development and contributes to the pathophysiology of the disease. However, the activation of endothelial β-catenin/TCF signaling and its role in fibronectin expression in atherosclerosis are not currently known. To assess the activity of β-catenin/TCF signaling in atherosclerosis development and its regulation of fibronectin in vascular endothelium. Histological staining identified preferential nuclear localization of β-catenin in the endothelium of atheroprone aorta prior to and during lesion development. Transgenic reporter studies revealed that increased levels of TCF transcriptional activity in endothelium correlated anatomically with β-catenin nuclear localization and fibronectin deposition. Exposure of endothelial cells to human-derived atheroprone shear stress induced nuclear localization of β-catenin, transcriptional activation of TCF, and expression of fibronectin. Activation of fibronectin expression required β-catenin, TCF and the transcriptional co-activator CBP. Finally, we identified PECAM-1as a critical regulator of constitutive β-catenin and GSK-3β activities. This data uncovers novel constitutive activation of the endothelial β-catenin/TCF signaling pathway in atherosclerosis and regulation of fibronectin through hemodynamic shear stress.