Bessler, Waylan K.Kim, GraceHudson, Farlyn Z.Mund, Julie A.Mali, RaghuveerMenon, KeshavKapur, ReubenClapp, D. WadeIngram Jr., David A.Stansfield, Brian K.2017-07-312017-07-312016-03-15Bessler, W. K., Kim, G., Hudson, F. Z., Mund, J. A., Mali, R., Menon, K., … Stansfield, B. K. (2016). Nf1+/− monocytes/macrophages induce neointima formation via CCR2 activation. Human Molecular Genetics, 25(6), 1129–1139. http://doi.org/10.1093/hmg/ddv635https://hdl.handle.net/1805/13648Persons with neurofibromatosis type 1 (NF1) have a predisposition for premature and severe arterial stenosis. Mutations in the NF1 gene result in decreased expression of neurofibromin, a negative regulator of p21(Ras), and increases Ras signaling. Heterozygous Nf1 (Nf1(+/-)) mice develop a marked arterial stenosis characterized by proliferating smooth muscle cells (SMCs) and a predominance of infiltrating macrophages, which closely resembles arterial lesions from NF1 patients. Interestingly, lineage-restricted inactivation of a single Nf1 allele in monocytes/macrophages is sufficient to recapitulate the phenotype observed in Nf1(+/-) mice and to mobilize proinflammatory CCR2+ monocytes into the peripheral blood. Therefore, we hypothesized that CCR2 receptor activation by its primary ligand monocyte chemotactic protein-1 (MCP-1) is critical for monocyte infiltration into the arterial wall and neointima formation in Nf1(+/-) mice. MCP-1 induces a dose-responsive increase in Nf1(+/-) macrophage migration and proliferation that corresponds with activation of multiple Ras kinases. In addition, Nf1(+/-) SMCs, which express CCR2, demonstrate an enhanced proliferative response to MCP-1 when compared with WT SMCs. To interrogate the role of CCR2 activation on Nf1(+/-) neointima formation, we induced neointima formation by carotid artery ligation in Nf1(+/-) and WT mice with genetic deletion of either MCP1 or CCR2. Loss of MCP-1 or CCR2 expression effectively inhibited Nf1(+/-) neointima formation and reduced macrophage content in the arterial wall. Finally, administration of a CCR2 antagonist significantly reduced Nf1(+/-) neointima formation. These studies identify MCP-1 as a potent chemokine for Nf1(+/-) monocytes/macrophages and CCR2 as a viable therapeutic target for NF1 arterial stenosis.en-USPublisher PolicyCarotid arteriesChemokine CCL2MacrophagesMonocytesNeointimaNeurofibromatosis 1Receptors, CCR2Article