[HTML][HTML] Macrophage LRP1 suppresses neo-intima formation during vascular remodeling by modulating the TGF-β signaling pathway

SC Muratoglu, S Belgrave, AP Lillis, M Migliorini… - PLoS …, 2011 - journals.plos.org
SC Muratoglu, S Belgrave, AP Lillis, M Migliorini, S Robinson, E Smith, L Zhang…
PLoS One, 2011journals.plos.org
Background Vascular remodeling in response to alterations in blood flow has been shown to
modulate the formation of neo-intima. This process results from a proliferative response of
vascular smooth muscle cells and is influenced by macrophages, which potentiate the
development of the intima. The LDL receptor-related protein 1 (LRP1) is a large endocytic
and signaling receptor that recognizes a number of ligands including apoE-containing
lipoproteins, proteases and protease-inhibitor complexes. Macrophage LRP1 is known to …
Background
Vascular remodeling in response to alterations in blood flow has been shown to modulate the formation of neo-intima. This process results from a proliferative response of vascular smooth muscle cells and is influenced by macrophages, which potentiate the development of the intima. The LDL receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that recognizes a number of ligands including apoE-containing lipoproteins, proteases and protease-inhibitor complexes. Macrophage LRP1 is known to influence the development of atherosclerosis, but its role in vascular remodeling has not been investigated.
Methodology/Principal Findings
To define the contribution of macrophage LRP1 to vascular remodeling, we generated macrophage specific LRP1-deficient mice (macLRP1-/-) on an LDL receptor (LDLr) knock-out background. Using a carotid ligation model, we detected a 2-fold increase in neointimal thickening and a 2-fold increase in the intima/media ratio in macLRP1-/- mice. Quantitative RT-PCR arrays of the remodeled vessel wall identified increases in mRNA levels of the TGF-β2 gene as well as the Pdgfa gene in macLRP1-/- mice which could account for the alterations in vascular remodeling. Immunohistochemistry analysis revealed increased activation of the TGF-β signaling pathway in macLRP1-/- mice. Further, we observed that LRP1 binds TGF-β2 and macrophages lacking LRP1 accumulate twice as much TGF-β2 in conditioned media. Finally, TNF-α modulation of the TGF-β2 gene in macrophages is attenuated when LRP1 is expressed. Together, the data reveal that LRP1 modulates both the expression and protein levels of TGF-β2 in macrophages.
Conclusions/Significance
Our data demonstrate that macrophage LRP1 protects the vasculature by limiting remodeling events associated with flow. This appears to occur by the ability of macrophage LRP1 to reduce TGF-β2 protein levels and to attenuate expression of the TGF-β2 gene resulting in suppression of the TGF-β signaling pathway.
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