title: Ras-Mek-Erk signaling regulates Nf1 heterozygous neointima formation.
abstract: Neurofibromatosis type 1 (NF1) results from mutations in the NF1 tumor-suppressor gene, which encodes neurofibromin, a negative regulator of diverse Ras signaling cascades. Arterial stenosis is a nonneoplastic manifestation of NF1 that predisposes some patients to debilitating morbidity and sudden death. Recent murine studies demonstrate that Nf1 heterozygosity (Nf1(+/-)) in monocytes/macrophages significantly enhances intimal proliferation after arterial injury. However, the downstream Ras effector pathway responsible for this phenotype is unknown. Based on in vitro assays demonstrating enhanced extracellular signal-related kinase (Erk) signaling in Nf1(+/-) macrophages and vascular smooth muscle cells and in vivo evidence of Erk amplification without alteration of phosphatidylinositol 3-kinase signaling in Nf1(+/-) neointimas, we tested the hypothesis that Ras-Erk signaling regulates intimal proliferation in a murine model of NF1 arterial stenosis. By using a well-established in vivo model of inflammatory cell migration and standard cell culture, neurofibromin-deficient macrophages demonstrate enhanced sensitivity to growth factor stimulation in vivo and in vitro, which is significantly diminished in the presence of PD0325901, a specific inhibitor of Ras-Erk signaling in phase 2 clinical trials for cancer. After carotid artery injury, Nf1(+/-) mice demonstrated increased intimal proliferation compared with wild-type mice. Daily administration of PD0325901 significantly reduced Nf1(+/-) neointima formation to levels of wild-type mice. These studies identify the Ras-Erk pathway in neurofibromin-deficient macrophages as the aberrant pathway responsible for enhanced neointima formation.
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pediatrics and Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Stansfield
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pediatrics and Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Waylan K
authors.initials: WK
authors.lastname: Bessler
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pediatrics and Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Raghuveer
authors.initials: R
authors.lastname: Mali
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pediatrics and Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Mund
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pediatrics and Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Brandon D
authors.initials: BD
authors.lastname: Downing
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pediatrics and Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Reuben
authors.initials: R
authors.lastname: Kapur
authors.affiliation: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pediatrics and Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address: dingram@iu.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Ingram
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016893:Carotid Stenosis / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D020935:MAP Kinase Signaling System / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D058426:Neointima / Q000378:metabolism / Q000473:pathology*; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology
chemical_list: D025542:Neurofibromin 1; D018631:ras Proteins