Hemodynamic Activation of β-Catenin and T-Cell-Specific Transcription Factor Signaling in Vascular Endothelium Regulates Fibronectin Expression

Objective-The goal of this study was to assess the activity of beta-catenin/T-cell-specific transcription factor (TCF) signaling in atherosclerosis development and its regulation of fibronectin in vascular endothelium. Methods and Results-Histological staining identified preferential nuclear localization of beta-catenin in the endothelium of atheroprone aorta before and during lesion development. Transgenic reporter studies revealed that increased levels of TCF transcriptional activity in endothelium correlated anatomically with beta-catenin nuclear localization and fibronectin deposition. Exposure of endothelial cells to human-derived atheroprone shear stress induced nuclear localization of beta-catenin, transcriptional activation of TCF, and expression of fibronectin. Activation of fibronectin expression required beta-catenin, TCF, and the transcriptional coactivator CRBP-binding protein. Finally, we identified platelet endothelial cell adhesion molecule-1 as a critical regulator of constitutive beta-catenin and glycogen synthase kinase-3 beta activities. Conclusion-These data reveal novel constitutive activation of the endothelial beta-catenin/TCF signaling pathway in atherosclerosis and regulation of fibronectin through hemodynamic shear stress. (Arterioscler Thromb Vasc Biol. 2011; 31:1625-1633.)