PMID- 24925976 OWN - NLM STAT- MEDLINE DCOM- 20140908 LR - 20220223 IS - 1524-4636 (Electronic) IS - 1079-5642 (Linking) VI - 34 IP - 8 DP - 2014 Aug TI - Nitric oxide prevents aortic neointimal hyperplasia by controlling macrophage polarization. PG - 1739-46 LID - 10.1161/ATVBAHA.114.303866 [doi] AB - OBJECTIVE: Nitric oxide synthase 3 (NOS3) prevents neointima hyperplasia by still unknown mechanisms. To demonstrate the significance of endothelial nitric oxide in the polarization of infiltrated macrophages through the expression of matrix metalloproteinase (MMP)-13 in neointima formation. APPROACH AND RESULTS: After aortic endothelial denudation, NOS3 null mice show elevated neointima formation, detecting increased mobilization of LSK (lineage-negative [Lin]-stem-cell antigen 1 [SCA1]+KIT+) progenitor cells, and high ratios of M1 (proinflammatory) to M2 (resolving) macrophages, accompanied by high expression of interleukin-5, interleukin-6, MCP-1 (monocyte chemoattractant protein), VEGF (vascular endothelial growth factor), GM-CSF (granulocyte-macrophage colony stimulating factor), interleukin-1beta, and interferon-gamma. In conditional c-Myc knockout mice, in which M2 polarization is defective, denuded aortas showed extensive wall thickening as well. Conditioned medium from NOS3-deficient endothelium induced extensive repolarization of M2 macrophages to an M1 phenotype, and vascular smooth muscle cells proliferated and migrated faster in conditioned medium from M1 macrophages. Among the different proteins participating in cell migration, MMP-13 was preferentially expressed by M1 macrophages. M1-mediated vascular smooth muscle cell migration was inhibited when macrophages were isolated from MMP-13-deficient mice, whereas exogenous administration of MMP-13 to vascular smooth muscle cell fully restored migration. Excess vessel wall thickening in mice lacking NOS3 was partially reversed by simultaneous deletion of MMP-13, indicating that NOS3 prevents neointimal hyperplasia by preventing MMP-13 activity. An excess of M1-polarized macrophages that coexpress MMP-13 was also detected in human carotid samples from endarterectomized patients. CONCLUSIONS: These findings indicate that at least M1 macrophage-mediated expression of MMP-13 in NOS3 null mice induces neointima formation after vascular injury, suggesting that MMP-13 may represent a new promising target in vascular disease. CI - (c) 2014 American Heart Association, Inc. FAU - Lavin, Begona AU - Lavin B AD - From the Fundacion Centro Nacional de Investigaciones Cardiovasculares CNIC Melchor Fernandez Almagro 3, Madrid, Spain (B.L., M.G., O.M.P., B.C., C.Z.); Departmento de Fisiologia, Facultad de Medicina, Universidad de Alcala, Ctra Madrid-Barcelona, Alcala de Henares, Spain (M.S.); and Facultad de Medicina, Universidad Francisco de Vitoria, Pozuelo de Alarcon, Madrid, Spain (M.J.P., C.Z.). FAU - Gomez, Monica AU - Gomez M AD - From the Fundacion Centro Nacional de Investigaciones Cardiovasculares CNIC Melchor Fernandez Almagro 3, Madrid, Spain (B.L., M.G., O.M.P., B.C., C.Z.); Departmento de Fisiologia, Facultad de Medicina, Universidad de Alcala, Ctra Madrid-Barcelona, Alcala de Henares, Spain (M.S.); and Facultad de Medicina, Universidad Francisco de Vitoria, Pozuelo de Alarcon, Madrid, Spain (M.J.P., C.Z.). FAU - Pello, Oscar M AU - Pello OM AD - From the Fundacion Centro Nacional de Investigaciones Cardiovasculares CNIC Melchor Fernandez Almagro 3, Madrid, Spain (B.L., M.G., O.M.P., B.C., C.Z.); Departmento de Fisiologia, Facultad de Medicina, Universidad de Alcala, Ctra Madrid-Barcelona, Alcala de Henares, Spain (M.S.); and Facultad de Medicina, Universidad Francisco de Vitoria, Pozuelo de Alarcon, Madrid, Spain (M.J.P., C.Z.). FAU - Castejon, Borja AU - Castejon B AD - From the Fundacion Centro Nacional de Investigaciones Cardiovasculares CNIC Melchor Fernandez Almagro 3, Madrid, Spain (B.L., M.G., O.M.P., B.C., C.Z.); Departmento de Fisiologia, Facultad de Medicina, Universidad de Alcala, Ctra Madrid-Barcelona, Alcala de Henares, Spain (M.S.); and Facultad de Medicina, Universidad Francisco de Vitoria, Pozuelo de Alarcon, Madrid, Spain (M.J.P., C.Z.). FAU - Piedras, Maria J AU - Piedras MJ AD - From the Fundacion Centro Nacional de Investigaciones Cardiovasculares CNIC Melchor Fernandez Almagro 3, Madrid, Spain (B.L., M.G., O.M.P., B.C., C.Z.); Departmento de Fisiologia, Facultad de Medicina, Universidad de Alcala, Ctra Madrid-Barcelona, Alcala de Henares, Spain (M.S.); and Facultad de Medicina, Universidad Francisco de Vitoria, Pozuelo de Alarcon, Madrid, Spain (M.J.P., C.Z.). FAU - Saura, Marta AU - Saura M AD - From the Fundacion Centro Nacional de Investigaciones Cardiovasculares CNIC Melchor Fernandez Almagro 3, Madrid, Spain (B.L., M.G., O.M.P., B.C., C.Z.); Departmento de Fisiologia, Facultad de Medicina, Universidad de Alcala, Ctra Madrid-Barcelona, Alcala de Henares, Spain (M.S.); and Facultad de Medicina, Universidad Francisco de Vitoria, Pozuelo de Alarcon, Madrid, Spain (M.J.P., C.Z.). FAU - Zaragoza, Carlos AU - Zaragoza C AD - From the Fundacion Centro Nacional de Investigaciones Cardiovasculares CNIC Melchor Fernandez Almagro 3, Madrid, Spain (B.L., M.G., O.M.P., B.C., C.Z.); Departmento de Fisiologia, Facultad de Medicina, Universidad de Alcala, Ctra Madrid-Barcelona, Alcala de Henares, Spain (M.S.); and Facultad de Medicina, Universidad Francisco de Vitoria, Pozuelo de Alarcon, Madrid, Spain (M.J.P., C.Z.). cpatitos@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140612 PL - United States TA - Arterioscler Thromb Vasc Biol JT - Arteriosclerosis, thrombosis, and vascular biology JID - 9505803 RN - 0 (Biomarkers) RN - 0 (Inflammation Mediators) RN - 0 (Myc protein, mouse) RN - 0 (Proto-Oncogene Proteins c-myc) RN - 31C4KY9ESH (Nitric Oxide) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 1.14.13.39 (Nos3 protein, mouse) RN - EC 3.4.24.- (Matrix Metalloproteinase 13) RN - EC 3.4.24.- (Mmp13 protein, mouse) SB - IM MH - Aged MH - Aged, 80 and over MH - Animals MH - Aorta/metabolism/pathology MH - Aortic Diseases/enzymology/genetics/*metabolism/pathology MH - Biomarkers/metabolism MH - Case-Control Studies MH - Cell Differentiation MH - Cell Lineage MH - Cell Movement MH - Cell Proliferation MH - Cells, Cultured MH - Disease Models, Animal MH - Female MH - Humans MH - Hyperplasia MH - Inflammation Mediators/metabolism MH - Macrophages/enzymology/*metabolism/pathology MH - Male MH - Matrix Metalloproteinase 13/deficiency/genetics MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Middle Aged MH - Muscle, Smooth, Vascular/enzymology/*metabolism/pathology MH - Myocytes, Smooth Muscle/enzymology/*metabolism/pathology MH - *Neointima MH - Nitric Oxide/*metabolism MH - Nitric Oxide Synthase Type III/deficiency/genetics MH - Phenotype MH - Proto-Oncogene Proteins c-myc/deficiency/genetics MH - Time Factors OTO - NOTNLM OT - angioplasty OT - entothelial nitric oxide synthase 3 OT - macrophage OT - matrix metalloproteinase-13 OT - neointima EDAT- 2014/06/14 06:00 MHDA- 2014/09/10 06:00 CRDT- 2014/06/14 06:00 PHST- 2014/06/14 06:00 [entrez] PHST- 2014/06/14 06:00 [pubmed] PHST- 2014/09/10 06:00 [medline] AID - ATVBAHA.114.303866 [pii] AID - 10.1161/ATVBAHA.114.303866 [doi] PST - ppublish SO - Arterioscler Thromb Vasc Biol. 2014 Aug;34(8):1739-46. doi: 10.1161/ATVBAHA.114.303866. Epub 2014 Jun 12.