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

-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 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 [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.)