Hemodynamic activation of beta-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 ß-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 ß-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 ß-catenin nuclear localization and fibronectin deposition. Exposure of endothelial cells to human-derived atheroprone shear stress induced nuclear localization of ß-catenin, transcriptional activation of TCF, and expression of fibronectin. Activation of fibronectin expression required ß-catenin, TCF, and the transcriptional coactivator CRBP-binding protein. Finally, we identified platelet endothelial cell adhesion molecule-1 as a critical regulator of constitutive ß-catenin and glycogen synthase kinase-3ß activities. CONCLUSIONS: These data reveal novel constitutive activation of the endothelial ß-catenin/TCF signaling pathway in atherosclerosis and regulation of fibronectin through hemodynamic shear stress.