LRP1 functions as an atheroprotective integrator of TGFbeta and PDFG signals in the vascular wall: implications for Marfan syndrome. - Archive ouverte HAL
Journal Articles PLoS ONE Year : 2007

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

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.

Dates and versions

hal-00190934 , version 1 (23-11-2007)

Identifiers

Cite

Philippe Boucher, Wei-Ping Li, Rachel L Matz, Yoshiharu Takayama, Johan Auwerx, et al.. LRP1 functions as an atheroprotective integrator of TGFbeta and PDFG signals in the vascular wall: implications for Marfan syndrome.. PLoS ONE, 2007, 2 (5), pp.e448. ⟨10.1371/journal.pone.0000448⟩. ⟨hal-00190934⟩
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