TY - JOUR
T1 - LRP1 functions as an atheroprotective integrator of TGFβ and PDGF signals in the vascular wall
T2 - Implications for Marfan syndrome
AU - Boucker, Philippe
AU - Li, Wei Ping
AU - Matz, Rachel L.
AU - Takayama, Yoshiharu
AU - Auwerx, Johan
AU - Anderson, Richard G W
AU - Herz, Joachim
PY - 2007/5/16
Y1 - 2007/5/16
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0000448
DO - 10.1371/journal.pone.0000448
M3 - Article
C2 - 17505534
AN - SCOPUS:44149093500
SN - 1932-6203
VL - 2
JO - PloS one
JF - PloS one
IS - 5
M1 - e448
ER -