Wild-type LRP6 inhibits, whereas atherosclerosis-linked LRP6R611C increases PDGF-dependent vascular smooth muscle cell proliferation

Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):1914-8. doi: 10.1073/pnas.1019443108. Epub 2011 Jan 18.

Abstract

Vascular smooth muscle cell (VSMC) proliferation is an important event in atherosclerosis and other vasculopathies. PDGF signaling is a key mediator of SMC proliferation, but the mechanisms that control its activity remain unclear. We previously identified a mutation in LDL receptor-related protein 6 (LRP6), LRP6(R611C), that causes early atherosclerosis. Examination of human atherosclerotic coronary arteries showed markedly increased expression of LRP6 and colocalization with PDGF receptor β (PDGFR-β). Further investigation showed that wild-type LRP6 inhibits but LRP6(R611C) promotes VSMC proliferation in response to PDGF. We found that wild-type LRP6 forms a complex with PDGFR-β and enhances its lysosomal degradation, functions that are severely impaired in LRP6(R611C). Further, we observed that wild-type and mutant LRP6 regulate cell-cycle activity by triggering differential effects on PDGF-dependent pathways. These findings implicate LRP6 as a critical modulator of PDGF-dependent regulation of cell cycle in smooth muscle and indicate that loss of this function contributes to development of early atherosclerosis in humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atherosclerosis / pathology
  • Atherosclerosis / physiopathology*
  • Cell Proliferation*
  • Cyclin D1 / metabolism
  • Humans
  • Immunohistochemistry
  • LDL-Receptor Related Proteins / physiology*
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Muscle, Smooth, Vascular / cytology*
  • Platelet-Derived Growth Factor / physiology*
  • RNA, Messenger / genetics
  • Receptor, Platelet-Derived Growth Factor beta / genetics
  • Signal Transduction

Substances

  • LDL-Receptor Related Proteins
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Platelet-Derived Growth Factor
  • RNA, Messenger
  • Cyclin D1
  • Receptor, Platelet-Derived Growth Factor beta