| First Author | Boucher P | Year | 2007 |
| Journal | PLoS One | Volume | 2 |
| Issue | 5 | Pages | e448 |
| PubMed ID | 17505534 | Mgi Jnum | J:129347 |
| Mgi Id | MGI:3769094 | Doi | 10.1371/journal.pone.0000448 |
| Citation | Boucher P, et al. (2007) LRP1 functions as an atheroprotective integrator of TGFbeta and PDFG signals in the vascular wall: implications for Marfan syndrome. PLoS One 2(5):e448 |
| abstractText | 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. |
