title: Macrophage LRP1 suppresses neo-intima formation during vascular remodeling by modulating the TGF-β signaling pathway.
abstract: 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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Maryland, United States of America.
authors.forename: Selen Catania
authors.initials: SC
authors.lastname: Muratoglu
authors.forename: Shani
authors.initials: S
authors.lastname: Belgrave
authors.forename: Anna P
authors.initials: AP
authors.lastname: Lillis
authors.forename: Mary
authors.initials: M
authors.lastname: Migliorini
authors.forename: Susan
authors.initials: S
authors.lastname: Robinson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Smith
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000473:pathology; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006965:Hyperplasia; D007150:Immunohistochemistry; D008026:Ligation; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000172:deficiency / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*; D020257:Ventricular Remodeling
chemical_list: D026503:Low Density Lipoprotein Receptor-Related Protein-1; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D020796:Receptor, Platelet-Derived Growth Factor alpha; D048049:Extracellular Signal-Regulated MAP Kinases