Hemodynamic Activation of β-Catenin and TCF Signaling in Vascular Endothelium Regulates Fibronectin Expression
Objective—The goal of this study was to assess the activity of β-catenin/TCF signaling in atherosclerosis development and its regulation of fibronectin in vascular endothelium.
Methods and Results—Histological staining identified preferential nuclear localization of β-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 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 coactivator CBP. Finally, we identified PECAM-1 as a critical regulator of constitutive β-catenin and glycogen synthase kinase-3β activities.
Conclusion—These data reveal novel constitutive activation of the endothelial β-catenin/TCF signaling pathway in atherosclerosis and regulation of fibronectin through hemodynamic shear stress.
- Received November 30, 2010.
- Accepted April 13, 2011.
- © 2011 American Heart Association, Inc.