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.