Ras-mek-erk signaling regulates Nf1 heterozygous neointima formation

Brian K. Stansfield, Waylan K. Bessler, Raghuveer Mali, Julie A. Mund, Brandon D. Downing, Reuben Kapur, David Ingram

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)79-85
Number of pages7
JournalAmerican Journal of Pathology
Volume184
Issue number1
DOIs
StatePublished - Jan 2014

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Neointima
Neurofibromatosis 1
Neurofibromin 1
Tunica Intima
Phosphotransferases
Macrophages
Pathologic Constriction
Carotid Artery Injuries
Phosphatidylinositol 3-Kinase
Sudden Death
Tumor Suppressor Genes
Vascular Smooth Muscle
Smooth Muscle Myocytes
Cell Movement
Monocytes
Intercellular Signaling Peptides and Proteins
Cell Culture Techniques
Clinical Trials
Morbidity
Phenotype

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Ras-mek-erk signaling regulates Nf1 heterozygous neointima formation. / Stansfield, Brian K.; Bessler, Waylan K.; Mali, Raghuveer; Mund, Julie A.; Downing, Brandon D.; Kapur, Reuben; Ingram, David.

In: American Journal of Pathology, Vol. 184, No. 1, 01.2014, p. 79-85.

Research output: Contribution to journalArticle

Stansfield, Brian K. ; Bessler, Waylan K. ; Mali, Raghuveer ; Mund, Julie A. ; Downing, Brandon D. ; Kapur, Reuben ; Ingram, David. / Ras-mek-erk signaling regulates Nf1 heterozygous neointima formation. In: American Journal of Pathology. 2014 ; Vol. 184, No. 1. pp. 79-85.
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