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

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Abstract
β-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 β-catenin and Tcf played a critical role in vascular remodeling. The first objective was to define β-catenin expression in vascular smooth muscle cells (VSMCs) after balloon injury. Indeed, β-catenin mRNA and protein were significantly elevated 7 days after balloon injury in the rat carotid artery. We hypothesized that β-catenin accumulation in response to vascular injury inhibited VSMC apoptosis. In line with our hypothesis, transfection of a degradation-resistant β-catenin transgene into rat VSMCs significantly inhibited apoptosis. Accumulation of β-catenin also resulted in a 10-fold increase in the activation of Tcf. To test if Tcf was necessary to confer β-catenin–induced survival, loss of function studies were carried out with a dominant negative Tcf-4 transgene lacking the β-catenin binding domain, Tcf4(N31). Indeed, loss of Tcf-4 activity abolished β-catenin–induced survival. We further postulated that β-catenin and Tcf promoted cell cycle progression by activating cyclin D1, a target gene of Tcf-4. β-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, β-catenin and Tcf-4 play a dual role in vascular remodeling by inhibiting VSMC apoptosis and promoting proliferation.