title: Nf1+/- monocytes/macrophages induce neointima formation via CCR2 activation.
abstract: Persons with neurofibromatosis type 1 (NF1) have a predisposition for premature and severe arterial stenosis. Mutations in the NF1 gene result in decreased expression of neurofibromin, a negative regulator of p21(Ras), and increases Ras signaling. Heterozygous Nf1 (Nf1(+/-)) mice develop a marked arterial stenosis characterized by proliferating smooth muscle cells (SMCs) and a predominance of infiltrating macrophages, which closely resembles arterial lesions from NF1 patients. Interestingly, lineage-restricted inactivation of a single Nf1 allele in monocytes/macrophages is sufficient to recapitulate the phenotype observed in Nf1(+/-) mice and to mobilize proinflammatory CCR2+ monocytes into the peripheral blood. Therefore, we hypothesized that CCR2 receptor activation by its primary ligand monocyte chemotactic protein-1 (MCP-1) is critical for monocyte infiltration into the arterial wall and neointima formation in Nf1(+/-) mice. MCP-1 induces a dose-responsive increase in Nf1(+/-) macrophage migration and proliferation that corresponds with activation of multiple Ras kinases. In addition, Nf1(+/-) SMCs, which express CCR2, demonstrate an enhanced proliferative response to MCP-1 when compared with WT SMCs. To interrogate the role of CCR2 activation on Nf1(+/-) neointima formation, we induced neointima formation by carotid artery ligation in Nf1(+/-) and WT mice with genetic deletion of either MCP1 or CCR2. Loss of MCP-1 or CCR2 expression effectively inhibited Nf1(+/-) neointima formation and reduced macrophage content in the arterial wall. Finally, administration of a CCR2 antagonist significantly reduced Nf1(+/-) neointima formation. These studies identify MCP-1 as a potent chemokine for Nf1(+/-) monocytes/macrophages and CCR2 as a viable therapeutic target for NF1 arterial stenosis.
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics and Neonatal-Perinatal Medicine and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Waylan K
authors.initials: WK
authors.lastname: Bessler
authors.affiliation: Department of Pediatrics and Neonatal-Perinatal Medicine and Vascular Biology Center, Augusta University, Augusta, GA 30912, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Kim
authors.affiliation: Department of Pediatrics and Neonatal-Perinatal Medicine and Vascular Biology Center, Augusta University, Augusta, GA 30912, USA.
authors.forename: Farlyn Z
authors.initials: FZ
authors.lastname: Hudson
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics and Neonatal-Perinatal Medicine and.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Mund
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics and Neonatal-Perinatal Medicine and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Raghuveer
authors.initials: R
authors.lastname: Mali
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics and Neonatal-Perinatal Medicine and.
authors.forename: Keshav
authors.initials: K
authors.lastname: Menon
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics and Neonatal-Perinatal Medicine and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics and Neonatal-Perinatal Medicine and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
authors.affiliation: Herman B. Wells Center for Pediatric Research, Department of Pediatrics and Neonatal-Perinatal Medicine and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Ingram
authors.affiliation: Department of Pediatrics and Neonatal-Perinatal Medicine and Vascular Biology Center, Augusta University, Augusta, GA 30912, USA bstansfield@gru.edu.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Stansfield
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D016514:Genes, Neurofibromatosis 1; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D058426:Neointima / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D025542:Neurofibromin 1 / Q000235:genetics; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D025542:Neurofibromin 1; D054390:Receptors, CCR2