title: Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo.
abstract: BACKGROUND
  Neurofibromatosis type 1 (NF1) is a genetic disorder resulting from mutations in the NF1 tumor suppressor gene. Neurofibromin, the protein product of NF1, functions as a negative regulator of Ras activity in circulating hematopoietic and vascular wall cells, which are critical for maintaining vessel wall homeostasis. NF1 patients have evidence of chronic inflammation resulting in the development of premature cardiovascular disease, including arterial aneurysms, which may manifest as sudden death. However, the molecular pathogenesis of NF1 aneurysm formation is unknown.
  
  
  RESULTS
  With the use of an angiotensin II-induced aneurysm model, we demonstrate that heterozygous inactivation of Nf1 (Nf1(+/-)) enhanced aneurysm formation with myeloid cell infiltration and increased oxidative stress in the vessel wall. Using lineage-restricted transgenic mice, we show that loss of a single Nf1 allele in myeloid cells is sufficient to recapitulate the Nf1(+/-) aneurysm phenotype in vivo. Finally, oral administration of simvastatin or the antioxidant apocynin reduced aneurysm formation in Nf1(+/-) mice.
  
  
  CONCLUSIONS
  These data provide genetic and pharmacological evidence that Nf1(+/-) myeloid cells are the cellular triggers for aneurysm formation in a novel model of NF1 vasculopathy and provide a potential therapeutic target.
authors.affiliation: Department of Pediatrics (F.L., B.D.D., L.C.S., J.A.M., M.R.D., W.K.B., K.N.S., D.M.H., J.C., D.W.C., S.J.C., B.K.S., D.A.I.), Wells Center for Pediatric Research (F.L., B.D.D., L.C.S., J.A.M., M.R.D., W.K.B., K.N.S., D.M.H., J.C., D.W.C., S.J.C., B.K.S., D.A.I.), Department of Biochemistry and Molecular Biology (B.D.D., D.W.C., S.J.C., D.A.I.), Microbiology and Immunology (M.R.D.), Pharmacology and Toxicology (L.M.K.), and Neurology (C.M.H.), Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.forename: Brandon D
authors.initials: BD
authors.lastname: Downing
authors.forename: Lucy C
authors.initials: LC
authors.lastname: Smiley
authors.forename: Julie A
authors.initials: JA
authors.lastname: Mund
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Distasi
authors.forename: Waylan K
authors.initials: WK
authors.lastname: Bessler
authors.forename: Kara N
authors.initials: KN
authors.lastname: Sarchet
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Hinds
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Kamendulis
authors.forename: Cynthia M
authors.initials: CM
authors.lastname: Hingtgen
authors.forename: Jamie
authors.initials: J
authors.lastname: Case
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Brian K
authors.initials: BK
authors.lastname: Stansfield
authors.forename: David A
authors.initials: DA
authors.lastname: Ingram
mesh_terms: D000783:Aneurysm / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism*; D025542:Neurofibromin 1 / Q000172:deficiency* / Q000235:genetics; D019821:Simvastatin / Q000627:therapeutic use
chemical_list: D025542:Neurofibromin 1; D019821:Simvastatin
keywords: Hydroxymethylglutaryl-CoA reductase inhibitors; aneurysm; antioxidants; genetics; inflammation; leukocytes; mice, transgenic