Begoña Lavin1, Monica Gómez1, Oscar M Pello1, Borja Castejon1, Maria J Piedras1, Marta Saura1, Carlos Zaragoza2. 1. From the Fundación 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 Fisiología, 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.). 2. From the Fundación 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 Fisiología, 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.
Abstract
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-1β, and interferon-γ. 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.
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-1β, and interferon-γ. 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.
Authors: Grant C Alexander; Jeremy B Vines; Patrick Hwang; Teayoun Kim; Jeong-a Kim; Brigitta C Brott; Young-Sup Yoon; Ho-Wook Jun Journal: ACS Appl Mater Interfaces Date: 2016-02-17 Impact factor: 9.229
Authors: Maria Grandoch; Jens W Fischer; Lena S Kiene; Susanne Homann; Tatsiana Suvorava; Berit Rabausch; Julia Müller; Georg Kojda; Inga Kretschmer; Sören Twarock; Guang Dai; René Deenen; Sonja Hartwig; Stefan Lehr; Karl Köhrer; Rashmin C Savani Journal: Arterioscler Thromb Vasc Biol Date: 2015-11-19 Impact factor: 8.311
Authors: Yao Wei Lu; Anthony M Lowery; Li-Yan Sun; Harold A Singer; Guohao Dai; Alejandro P Adam; Peter A Vincent; John J Schwarz Journal: Arterioscler Thromb Vasc Biol Date: 2017-05-04 Impact factor: 8.311
Authors: Ashraf Ul Kabir; Madhav Subramanian; Dong Hun Lee; Xiaoli Wang; Karen Krchma; Jun Wu; Teri Naismith; Carmen M Halabi; Ju Young Kim; Fadi E Pulous; Brian G Petrich; Suhyun Kim; Hae-Chul Park; Phyllis I Hanson; Hua Pan; Samuel A Wickline; Daved H Fremont; Changwon Park; Kyunghee Choi Journal: Sci Transl Med Date: 2021-03-03 Impact factor: 17.956