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


RESULTS
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
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.
Boucher
Philippe
P
Institut Gilbert-Laustriat, UMR 7175 LC-1, Department of Pharmacology; Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Medicale/Université Louis Pasteur, Illkirch, France.
Li
Wei-Ping
WP
Matz
Rachel L
RL
Takayama
Yoshiharu
Y
Auwerx
Johan
J
Anderson
Richard G W
RG
Herz
Joachim
J
D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control; D015153:Blotting, Western; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000502:physiology*; D008382:Marfan Syndrome / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D000077154:Rosiglitazone; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism*
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D010982:Platelet-Derived Growth Factor; D051785:Smad Proteins; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D000077154:Rosiglitazone