Abstract
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/β-catenin/T cell factor 4 (Tcf-4) cascade in the vasculature. This hypothesis was based on our previous work demonstrating a role for the β-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 (LRP6ΔC) abolished Tcf activity. LRP6-induced stimulation of Tcf was blocked in VSMCs harboring constitutive expression of a dominant negative Tcf-4 transgene lacking the β-catenin binding domain, suggesting that LRP6-induced activation of Tcf was mediated through a β-catenin-dependent signal. Expression of the dominant interfering LRP6ΔC transgene was sufficient to abolish the Wnt-induced survival as well as cyclin D, 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.
Original language | English (US) |
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Pages (from-to) | H2376-H2383 |
Journal | American Journal of Physiology - Heart and Circulatory Physiology |
Volume | 287 |
Issue number | 6 56-6 |
DOIs | |
State | Published - Dec 2004 |
Keywords
- Apoptosis
- Cyclin D
- T cell factor-4
- β-catenin