LRP1 functions as an atheroprotective integrator of TGFbeta and PDFG signals in the vascular wall: implications for Marfan syndrome

PLoS One. 2007 May 16;2(5):e448. doi: 10.1371/journal.pone.0000448.

Abstract

Background: The multifunctional receptor LRP1 controls expression, activity and trafficking of the PDGF receptor-beta in vascular smooth muscle cells (VSMC). LRP1 is also a receptor for TGFbeta1 and is required for TGFbeta mediated inhibition of cell proliferation.

Methods and principal findings: We show that loss of LRP1 in VSMC (smLRP(-)) in vivo results in a Marfan-like syndrome with nuclear accumulation of phosphorylated Smad2/3, disruption of elastic layers, tortuous aorta, and increased expression of the TGFbeta target genes thrombospondin-1 (TSP1) and PDGFRbeta in the vascular wall. Treatment of smLRP1(-) animals with the PPARgamma agonist rosiglitazone abolished nuclear pSmad accumulation, reversed the Marfan-like phenotype, and markedly reduced smooth muscle proliferation, fibrosis and atherosclerosis independent of plasma cholesterol levels.

Conclusions and significance: Our findings are consistent with an activation of TGFbeta signals in the LRP1-deficient vascular wall. LRP1 may function as an integrator of proliferative and anti-proliferative signals that control physiological mechanisms common to the pathogenesis of Marfan syndrome and atherosclerosis, and this is essential for maintaining vascular wall integrity.

Publication types

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

MeSH terms

  • Animals
  • Atherosclerosis / prevention & control
  • Blotting, Western
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-1 / physiology*
  • Marfan Syndrome / physiopathology*
  • Mice
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Platelet-Derived Growth Factor / metabolism*
  • Rosiglitazone
  • Signal Transduction
  • Smad Proteins / metabolism
  • Thiazolidinediones / pharmacology
  • Transforming Growth Factor beta / metabolism*
  • Tunica Intima / drug effects
  • Tunica Intima / metabolism*

Substances

  • Low Density Lipoprotein Receptor-Related Protein-1
  • Platelet-Derived Growth Factor
  • Smad Proteins
  • Thiazolidinediones
  • Transforming Growth Factor beta
  • Rosiglitazone