Circulation Research. 2002
Published online before print January 3, 2002, doi: 10.1161/hh0302.104466
Published online before print January 3, 2002, doi: 10.1161/hh0302.104466
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Submitted on June 7, 2001
Revised on December 19, 2001
Accepted on December 19, 2001
A Role for the ß-Catenin/T-Cell Factor Signaling Cascade in Vascular Remodeling
From the Lillehei Heart Institute, University of Minnesota, Minneapolis, Minn.
* To whom correspondence should be addressed. E-mail: Hallx068{at}umn.edu.
ß-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 ß-catenin and Tcf played a critical role in vascular remodeling. The first objective was to define ß-catenin expression in vascular smooth muscle cells (VSMCs) after balloon injury. Indeed, ß-catenin mRNA and protein were significantly elevated 7 days after balloon injury in the rat carotid artery. We hypothesized that ß-catenin accumulation in response to vascular injury inhibited VSMC apoptosis. In line with our hypothesis, transfection of a degradation-resistant ß-catenin transgene into rat VSMCs significantly inhibited apoptosis. Accumulation of ß-catenin also resulted in a 10-fold increase in the activation of Tcf. To test if Tcf was necessary to confer ß-catenin--induced survival, loss of function studies were carried out with a dominant negative Tcf-4 transgene lacking the ß-catenin binding domain, Tcf4(N31). Indeed, loss of Tcf-4 activity abolished ß-catenin--induced survival. We further postulated that ß-catenin and Tcf promoted cell cycle progression by activating cyclin D1, a target gene of Tcf-4. ß-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, ß-catenin and Tcf-4 play a dual role in vascular remodeling by inhibiting VSMC apoptosis and promoting proliferation.
Key words: vascular smooth muscle cells • apoptosis • proliferation • vascular injury
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