Stansfield, Brian K.Bessler, Waylan K.Mali, RaghuveerMund, Julie A.Downing, Brandon D.Kapur, ReubenIngram, David A. Jr2016-02-222016-02-222014-01Stansfield, B. K., Bessler, W. K., Mali, R., Mund, J. A., Downing, B. D., Kapur, R., & Ingram, D. A. (2014). Ras-Mek-Erk Signaling Regulates Nf1 Heterozygous Neointima Formation. The American Journal of Pathology, 184(1), 79–85. http://doi.org/10.1016/j.ajpath.2013.09.022https://hdl.handle.net/1805/8422Neurofibromatosis 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.en-USPublisher PolicyAnimalsBlotting, WesternCarotid StenosisDisease Models, AnimalMAP Kinase Signaling SystemMacrophagesMiceMice, Inbred C57BLMice, Mutant StrainsNeointimaNeurofibromatosis 1Neurofibromin 1Signal Transductionras ProteinsArticle