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Am J Physiol Heart Circ Physiol (July 22, 2004). doi:10.1152/ajpheart.01173.2003
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Submitted on December 15, 2003
Accepted on July 20, 2004

The LDL Receptor Related Protein LRP6 Regulates Proliferation and Survival Through the Wnt Cascade in Vascular Smooth Muscle Cells

Xiaohong Wang1, Neeta Adhikari1, Qinglu Li1, and Jennifer L Hall1*

1 Medicine - Cardiology, Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, USA

* To whom correspondence should be addressed. E-mail: hallx068{at}umn.edu.

Initial studies established expression of the novel low density lipoprotein (LDL) receptor related protein 6 (LRP6) in vascular smooth muscle cells (VSMC). We hypothesized that LRP6 was a critical mediator governing the regulation of the canonical Wnt/{beta}-catenin/(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 up-regulation significantly increased Wnt-1-induced Tcf activation. Moreover, a dominant interfering LRP6 mutant lacking the carboxyl intracellular domain (LRP6deltaC) abolished Tcf activity. LRP6 induced stimulation of Tcf was blocked in VSMC harboring constitutive expression of a dominant negative Tcf-4 transgene lacking the {beta}-catenin binding domain (Tcf-4(N31). This suggested that LRP6-induced activation of Tcf was mediated through a {beta}-catenin-dependent signal. Expression of the dominant interfering LRP6deltaC 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 growth and fate through the evolutionary conserved Wnt signaling cascade.




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