A Role for the beta-Catenin/T-Cell Factor Signaling Cascade in Vascular Remodeling

X. Wang
2002 Circulation Research  
␤-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 ␤-catenin and Tcf played a critical role in vascular remodeling. The first objective was to define ␤-catenin expression in vascular smooth muscle cells (VSMCs) after balloon injury. Indeed, ␤-catenin mRNA and protein were significantly elevated 7 days after balloon injury in the rat carotid artery. We
more » ... hypothesized that ␤-catenin accumulation in response to vascular injury inhibited VSMC apoptosis. In line with our hypothesis, transfection of a degradation-resistant ␤-catenin transgene into rat VSMCs significantly inhibited apoptosis. Accumulation of ␤-catenin also resulted in a 10-fold increase in the activation of Tcf. To test if Tcf was necessary to confer ␤-catenin-induced survival, loss of function studies were carried out with a dominant negative Tcf-4 transgene lacking the ␤-catenin binding domain, Tcf4(N31). Indeed, loss of Tcf-4 activity abolished ␤-catenin-induced survival. We further postulated that ␤-catenin and Tcf promoted cell cycle progression by activating cyclin D1, a target gene of Tcf-4. ␤-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 [ 3 H]thymidine incorporation and partial blockade of the G1-S phase transition. In conclusion, ␤-catenin and Tcf-4 play a dual role in vascular remodeling by inhibiting VSMC apoptosis and promoting proliferation. (Circ Res. 2002;90:340-347.)
doi:10.1161/hh0302.104466 pmid:11861424 fatcat:5wv7xm4tt5d2dpo2uyeotgivnq