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Am J Physiol Heart Circ Physiol 287: H2376-H2383, 2004. First published July 22, 2004; doi:10.1152/ajpheart.01173.2003
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LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells

Xiaohong Wang, Neeta Adhikari, Qinglu Li, and Jennifer L. Hall

Lillehei Heart Institute, Division of Cardiology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455

Submitted 15 December 2003 ; accepted in final form 20 July 2004

Initial studies have established expression of low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) in vascular smooth muscle cells (VSMCs). We hypothesized that LRP6 is a critical mediator governing the regulation of the canonical Wnt/{beta}-catenin/T cell factor 4 (Tcf-4) cascade in the vasculature. This hypothesis was based on our previous work demonstrating a role for the {beta}-catenin/Tcf-4 pathway in vascular remodeling as well as work in other cell systems establishing a role for LRP family members in the Wnt cascade. In line with our hypothesis, LRP6 upregulation significantly increased Wnt-1-induced Tcf activation. Moreover, a dominant interfering LRP6 mutant lacking the carboxyl intracellular domain (LRP6{Delta}C) abolished Tcf activity. LRP6-induced stimulation of Tcf was blocked in VSMCs harboring constitutive expression of a dominant negative Tcf-4 transgene lacking the {beta}-catenin binding domain, suggesting that LRP6-induced activation of Tcf was mediated through a {beta}-catenin-dependent signal. Expression of the dominant interfering LRP6{Delta}C transgene was sufficient to abolish the Wnt-induced survival as well as cyclin D1 activity and cell cycle progression. In conclusion, these findings provide the first evidence of a role for an LDL receptor-related protein in the regulation of VSMC proliferation and survival through the evolutionary conserved Wnt signaling cascade.

{beta}-catenin; apoptosis; cyclin D1; T cell factor-4


Address for reprint requests and other correspondence: J. L. Hall, Lillehei Heart Institute, Univ. of Minnesota, 420 Delaware St., Minneapolis, MN 55455 (E-mail: Hallx068{at}umn.edu)




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