LRP1 functions as an atheroprotective integrator of TGFβ and PDGF signals in the vascular wall: Implications for Marfan syndrome

Philippe Boucker, Wei Ping Li, Rachel L. Matz, Yoshiharu Takayama, Johan Auwerx, Richard G W Anderson, Joachim Herz

Research output: Contribution to journalArticle

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Abstract

Background. The multifunctional receptor LRP1 controls expression, activity and trafficking of the PDGF receptor-β in vascular smooth muscle cells (VSMC). LRP1 is also a receptor for TGFβ1 and is required for TGFβ mediated inhibition of cell proliferation. Methods and Principal Findings. We show that loss of LRP1 in VSMC (smLRP2) 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 TGFb target genes thrombospondin-1 (TSP1) and PDGFRβ in the vascular wall. Treatment of smLRP1 animals with the PPARγ 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 TGFβ 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.

Original languageEnglish (US)
Article numbere448
JournalPLoS One
Volume2
Issue number5
DOIs
StatePublished - May 16 2007

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Marfan Syndrome
blood vessels
Blood Vessels
Muscle
rosiglitazone
Vascular Smooth Muscle
Smooth Muscle Myocytes
smooth muscle
Atherosclerosis
Thrombospondin 1
Platelet-Derived Growth Factor Receptors
Peroxisome Proliferator-Activated Receptors
atherosclerosis
myocytes
Cell proliferation
Smooth Muscle
Aorta
Animals
Fibrosis
Genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

LRP1 functions as an atheroprotective integrator of TGFβ and PDGF signals in the vascular wall : Implications for Marfan syndrome. / Boucker, Philippe; Li, Wei Ping; Matz, Rachel L.; Takayama, Yoshiharu; Auwerx, Johan; Anderson, Richard G W; Herz, Joachim.

In: PLoS One, Vol. 2, No. 5, e448, 16.05.2007.

Research output: Contribution to journalArticle

Boucker, Philippe ; Li, Wei Ping ; Matz, Rachel L. ; Takayama, Yoshiharu ; Auwerx, Johan ; Anderson, Richard G W ; Herz, Joachim. / LRP1 functions as an atheroprotective integrator of TGFβ and PDGF signals in the vascular wall : Implications for Marfan syndrome. In: PLoS One. 2007 ; Vol. 2, No. 5.
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