| First Author | Muratoglu SC | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 12 | Pages | e28846 |
| PubMed ID | 22174911 | Mgi Jnum | J:182253 |
| Mgi Id | MGI:5315064 | Doi | 10.1371/journal.pone.0028846 |
| Citation | Muratoglu SC, et al. (2011) Macrophage LRP1 suppresses neo-intima formation during vascular remodeling by modulating the TGF-beta signaling pathway. PLoS One 6(12):e28846 |
| abstractText | 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-beta2 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-beta2 and macrophages lacking LRP1 accumulate twice as much TGF-beta2 in conditioned media. Finally, TNF-alpha modulation of the TGF-beta2 gene in macrophages is attenuated when LRP1 is expressed. Together, the data reveal that LRP1 modulates both the expression and protein levels of TGF-beta2 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-beta2 protein levels and to attenuate expression of the TGF-beta2 gene resulting in suppression of the TGF-beta signaling pathway. |
