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/-catenin/(Tcf-4) cascade in the vasculature. This hypothesis was based on our previous work demonstrating a role for the -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 -catenin binding domain (Tcf-4(N31). This suggested that LRP6-induced activation of Tcf was mediated through a -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.