title: Hemodynamic activation of beta-catenin and T-cell-specific transcription factor signaling in vascular endothelium regulates fibronectin expression.
abstract: 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.
  
  
  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.affiliation: Department of Biomedical Engineering, Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Gelfand
authors.forename: Julia
authors.initials: J
authors.lastname: Meller
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Pryor
authors.forename: Michael
authors.initials: M
authors.lastname: Kahn
authors.forename: Pamela D Schoppee
authors.initials: PD
authors.lastname: Bortz
authors.forename: Brian R
authors.initials: BR
authors.lastname: Wamhoff
authors.forename: Brett R
authors.initials: BR
authors.lastname: Blackman
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism*; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006439:Hemodynamics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013314:Stress, Mechanical; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D005353:Fibronectins; D016328:NF-kappa B; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D051820:TCF Transcription Factors; D051176:beta Catenin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3