OBJECTIVE: The goal of this study was to assess the activity of β-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 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 CRBP-binding protein. Finally, we identified platelet endothelial cell adhesion molecule-1 as a critical regulator of constitutive β-catenin and glycogen synthase kinase-3β activities. CONCLUSIONS: These data reveal novel constitutive activation of the endothelial β-catenin/TCF signaling pathway in atherosclerosis and regulation of fibronectin through hemodynamic shear stress.
OBJECTIVE: The goal of this study was to assess the activity of β-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 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 CRBP-binding protein. Finally, we identified platelet endothelial cell adhesion molecule-1 as a critical regulator of constitutive β-catenin and glycogen synthase kinase-3β activities. CONCLUSIONS: These data reveal novel constitutive activation of the endothelial β-catenin/TCF signaling pathway in atherosclerosis and regulation of fibronectin through hemodynamic shear stress.
Authors: Stijn P De Langhe; Frédéric G Sala; Pierre-Marie Del Moral; Timothy J Fairbanks; Kenneth M Yamada; David Warburton; Robert C Burns; Saverio Bellusci Journal: Dev Biol Date: 2005-01-15 Impact factor: 3.582
Authors: T C He; A B Sparks; C Rago; H Hermeking; L Zawel; L T da Costa; P J Morin; B Vogelstein; K W Kinzler Journal: Science Date: 1998-09-04 Impact factor: 47.728
Authors: A Wayne Orr; John M Sanders; Melissa Bevard; Elizabeth Coleman; Ian J Sarembock; Martin Alexander Schwartz Journal: J Cell Biol Date: 2005-04-04 Impact factor: 10.539
Authors: Zaki Al-Yafeai; Arif Yurdagul; Jonette M Peretik; Mabruka Alfaidi; Patrick A Murphy; A Wayne Orr Journal: Arterioscler Thromb Vasc Biol Date: 2018-11 Impact factor: 8.311