Circulation Research. 2002;90:340-347
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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© 2002 American Heart Association, Inc.
Molecular Medicine |
A Role for the ß-Catenin/T-Cell Factor Signaling Cascade in Vascular Remodeling
From the Cardiovascular Research Institute (X.W., Y.X., Y.M., Y.Z., J.L.H.), Morehouse School of Medicine, Atlanta, Ga; the Division of Cardiology, Department of Medicine (X.W., J.L.H.), Lillehei Heart Institute, University of Minnesota, Minneapolis, Minn; and the Department of Pharmacology and Toxicology (W.M.B.), Maastricht University, Maastricht, The Netherlands.
Correspondence to Jennifer L. Hall, PhD, Assistant Professor of Medicine, Cardiovascular Division, Lillehei Heart Institute, University of Minnesota, 420 Delaware St, Minneapolis, MN 55455. 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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