Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo

Fang Li, Brandon D. Downing, Lucy C. Smiley, Julie A. Mund, Matthew R. DiStasi, Waylan K. Bessler, Kara N. Sarchet, Daniel M. Hinds, Lisa M. Kamendulis, Cynthia M. Hingtgen, Jamie Case, D. Wade Clapp, Simon J. Conway, Brian Kevin Stansfield, David A. Ingram

Research output: Contribution to journalArticle

14 Scopus citations

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. Method and 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)1213-1224
Number of pages12
JournalCirculation
Volume129
Issue number11
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Keywords

  • Aneurysm
  • Antioxidants
  • Genetics
  • Hydroxymethylglutaryl-CoA reductase inhibitors
  • Inflammation
  • Leukocytes
  • Mice
  • Transgenic

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Li, F., Downing, B. D., Smiley, L. C., Mund, J. A., DiStasi, M. R., Bessler, W. K., Sarchet, K. N., Hinds, D. M., Kamendulis, L. M., Hingtgen, C. M., Case, J., Clapp, D. W., Conway, S. J., Stansfield, B. K., & Ingram, D. A. (2014). Neurofibromin-deficient myeloid cells are critical mediators of aneurysm formation in vivo. Circulation, 129(11), 1213-1224. https://doi.org/10.1161/CIRCULATIONAHA.113.006320