A role for the beta-catenin/T-cell factor signaling cascade in vascular remodeling.
Beta-catenin and T cell factor (Tcf) are distal components of the highly conserved Wnt pathway that govern cell fate and proliferation in lower organisms. Thus, we hypothesized that the regulation of beta-catenin and Tcf played a critical role in vascular remodeling. The first objective was to define beta-catenin expression in vascular smooth muscle cells (VSMCs) after balloon injury. Indeed, beta-catenin mRNA and protein were significantly elevated 7 days after balloon injury in the rat carotid artery. We hypothesized that beta-catenin accumulation in response to vascular injury inhibited VSMC apoptosis. In line with our hypothesis, transfection of a degradation-resistant beta-catenin transgene into rat VSMCs significantly inhibited apoptosis. Accumulation of beta-catenin also resulted in a 10-fold increase in the activation of Tcf. To test if Tcf was necessary to confer beta-catenin-induced survival, loss of function studies were carried out with a dominant negative Tcf-4 transgene lacking the beta-catenin binding domain, Tcf4(N31). Indeed, loss of Tcf-4 activity abolished beta-catenin-induced survival. We further postulated that beta-catenin and Tcf promoted cell cycle progression by activating cyclin D1, a target gene of Tcf-4. Beta-catenin activated cyclin D1, and this activation was partially blocked with loss of Tcf-4. In parallel, blockade of Tcf-4 resulted in inhibition of [3H]thymidine incorporation and partial blockade of the G1-S phase transition. In conclusion, beta-catenin and Tcf-4 play a dual role in vascular remodeling by inhibiting VSMC apoptosis and promoting proliferation.
Wang
Xiaohong
X
Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Ga, USA.
Xiao
Yan
Y
Mou
Yongshan
Y
Zhao
Ying
Y
Blankesteijn
W Matthijs
WM
Hall
Jennifer L
JL
D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D016893:Carotid Stenosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002404:Catheterization / Q000009:adverse effects; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D005799:Genes, Dominant; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes; D015854:Up-Regulation / Q000502:physiology; D051176:beta Catenin
C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D012333:RNA, Messenger; D051820:TCF Transcription Factors; C553059:Tcf7l2 protein, rat; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3