LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells

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

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

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 languageEnglish (US)
Pages (from-to)H2376-H2383
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume287
Issue number6 56-6
DOIs
StatePublished - Dec 2004

Keywords

  • Apoptosis
  • Cyclin D
  • T cell factor-4
  • β-catenin

Fingerprint Dive into the research topics of 'LDL receptor-related protein LRP6 regulates proliferation and survival through the Wnt cascade in vascular smooth muscle cells'. Together they form a unique fingerprint.

Cite this