Macrophage LRP1 Suppresses Neo-Intima Formation during Vascular Remodeling by Modulating the TGF-beta Signaling Pathway

作者：Muratoglu Selen Catania^*; Belgrave Shani; Lillis Anna P; Migliorini Mary; Robinson Susan; Smith Elizabeth; Zhang Li; Strickland Dudley K

来源：PLos One, 2011, 6(12): e28846.

DOI：10.1371/journal.pone.0028846

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-beta 2 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-beta signaling pathway in macLRP1-/- mice. Further, we observed that LRP1 binds TGF-beta 2 and macrophages lacking LRP1 accumulate twice as much TGF-beta 2 in conditioned media. Finally, TNF-alpha modulation of the TGF-beta 2 gene in macrophages is attenuated when LRP1 is expressed. Together, the data reveal that LRP1 modulates both the expression and protein levels of TGF-beta 2 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-beta 2 protein levels and to attenuate expression of the TGF-beta 2 gene resulting in suppression of the TGF-beta signaling pathway.

• 出版日期2011-12-9