Atherosclerotic remodeling in carotid plaques: the role of matrix metalloproteinases-2 and -9 and vascular smooth muscle cells of distinct phenotype
Keywords:
carotid atherosclerosis, vascular remodeling, smooth muscle cells, matrix metalloproteinases, MMP-2, MMP-9, CD68, RUNX2
Abstract
Aim. To study prevalence and localization of different phenotypes of vascular smooth muscle cells (VSMCs) in carotid atherosclerotic plaques and to examine expression of matrix metalloproteinase (MMP)-2 and MMP-9 in relation to different cell populations within the neointima.
Methods. The immunohistochemical examination was performed on 16 atherosclerotic plaques (8 unstable and 8 stable) excised during carotid endarterectomy for critical stenosis. VSMCs of contractile, synthetic, macrophagic, and osteogenic phenotypes were identified by staining for α-smooth muscle actin (α-SMA), vimentin, CD68, and RUNX2, respectively. Activity of neointimal remodeling was assessed by staining for MMP-2 and MMP-9.
Results. Approximately one-third of atherosclerotic plaques was positively stained for MMP-9 exclusively expressed in CD68-positive cells, which however, did not correlate with plaque ruptures. Localization, content, and ratio of different VSCM phenotypes significantly varied in different plaques. Positive α-SMA staining was found mainly in the intact media and fibrous cap. In contrast, both CD68-positive and CD68/α-SMA double-positive cells were detected within the neointima but not in the media. Vimentin was expressed in the neointima between the medial layers and fibrous cap near the acellular extracellular matrix suggesting its active production by mesenchymal cells. Both RUNX2- and RUNX2 α-SMA double-positive cells indicative of VSMC osteogenic differentiation were also observed in the neointima.
Conclusion. Carotid atherosclerotic plaques contained VSMCs of all phenotypes, which were differentially localized within the neointima; however, the MMP-2 and MMP-9 expression was restricted to CD68-positive macrophages and CD68/α-SMA-positive VSMCs of the macrophagal phenotype.
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5. Ruddy J.M., Ikonomidis J.S., Jones J.A. Multidimensional Contribution of Matrix Metalloproteinases to Atherosclerotic Plaque Vulnerability: Multiple Mechanisms of Inhibition to Promote Stability. J. Vasc. Res. 2016; 53(1-2): 1-16. doi: 10.1159/000446703.
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8. Page-McCaw A., Ewald A.J., Werb Z. Matrix metalloproteinases and the regulation of tissue remodelling. Nat. Rev. Mol. Cell Biol. 2007; 8(3): 221-233. doi: 10.1038/nrm2125.
9. Nagase H., Visse R., Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc. Res. 2006; 69(3): 562-573. doi: 10.1016/j.cardiores.2005.12.002.
10. Durham A.L., Speer M.Y., Scatena M., Giachelli C.M., Shanahan C.M. Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. Cardiovasc. Res. 2018; 114(4): 590-600. doi: 10.1093/cvr/cvy010.
11. Allahverdian S., Chaabane C., Boukais K., Francis G.A., Bochaton-Piallat M.L. Smooth muscle cell fate and plasticity in atherosclerosis. Cardiovasc. Res. 2018; 114(4): 540-550. doi: 10.1093/cvr/cvy022.
12. Chistiakov D.A., Orekhov A.N., Bobryshev Y.V. Vascular smooth muscle cell in atherosclerosis. Acta Physiol. (Oxf). 2015; 214(1): 33-50. doi: 10.1111/apha.12466.
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14. Salabei J.K., Hill B.G. Autophagic regulation of smooth muscle cell biology. Redox Biol. 2015; 4: 97-103. doi: 10.1016/j.redox.2014.12.007.
15. Chaabane C., Coen M., Bochaton-Piallat M.L. Smooth muscle cell phenotypic switch: implications for foam cell formation. Curr. Opin. Lipidol. 2014; 25(5): 374-379. doi: 10.1097/MOL.0000000000000113.
16. Skalen K., Gustafsson M., Rydberg E.K., Hulten L.M., Wiklund O., Innerarity T.L. et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature. 2002; 417(6890): 750-754. doi: 10.1038/nature00804.
17. Öörni K., Rajamäki K., Nguyen S.D., Lähdesmäki K., Plihtari R., Lee-Rueckert M. et al. Acidification of the intimal fluid: the perfect storm for atherogenesis. J. Lipid Res. 2015; 56(2): 203-214. doi: 10.1194/jlr.R050252.
18. Allahverdian S., Chehroudi A.C., McManus B.M., Abraham T., Francis G.A. Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation. 2014; 129(15): 1551-1559. doi: 10.1161/CIRCULATIONAHA.113.005015.
19. Shankman L.S., Gomez D., Cherepanova O.A., Salmon M., Alencar G.F., Haskins R.M. et al. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat. Med. 2015; 21(6): 628-637. doi: 10.1038/nm.3866.
20. Pryma C.S., Ortega C., Dubland J.A., Francis G.A. Pathways of smooth muscle foam cell formation in atherosclerosis. Curr. Opin. Lipidol. 2019; 30(2): 117-124. doi: 10.1097/MOL.0000000000000574.
21. Naik V., Leaf E.M., Hu J.H., Yang H.Y., Nguyen N.B., Giachelli C.M. et al. Sources of cells that contribute to atherosclerotic intimal calcification: an in vivo genetic fate mapping study. Cardiovasc. Res. 2012; 94(3): 545-554. doi: 10.1093/cvr/cvs126.
22. Nguyen N., Naik V., Speer M.Y. Diabetes mellitus accelerates cartilaginous metaplasia and calcification in atherosclerotic vessels of LDLr mutant mice. Cardiovasc. Pathol. 2013; 22(2): 167-175. doi: 10.1016/j.carpath.2012.06.007.
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25. Sluijter J.P., Pulskens W.P., Schoneveld A.H., Velema E., Strijder C.F., Moll F. et al. Matrix metalloproteinase 2 is associated with stable and matrix metalloproteinases 8 and 9 with vulnerable carotid atherosclerotic lesions: a study in human endarterectomy specimen pointing to a role for different extracellular matrix metalloproteinase inducer glycosylation forms. Stroke. 2006; 37(1): 235-239. doi: 10.1161/01.STR.0000196986.50059.e0.
26. Luttun A., Lutgens E., Manderveld A., Maris K., Collen D., Carmeliet P. et al. Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation. 2004; 109(11): 1408-1414. doi: 10.1161/01.CIR.0000121728.14930.DE.
27. Loftus I.M., Naylor A.R., Goodall S., Crowther M., Jones L., Bell P.R. et al. Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in acute plaque disruption. Stroke. 2000; 31(1): 40-47. doi: 10.1161/01.STR.31.1.40.
28. Johnson J.L., George S.J., Newby A.C., Jackson C.L. Divergent effects of matrix metalloproteinases 3, 7, 9, and 12 on atherosclerotic plaque stability in mouse brachiocephalic arteries. Proc. Natl. Acad. Sci. U S A. 2005; 102(43): 15575-15580. doi: 10.1073/pnas.0506201102.
Published
2020-11-26
How to Cite
Bogdanov L., Velikanova E., Shishkova D., Shabaev A., Kutikhin A. Atherosclerotic remodeling in carotid plaques: the role of matrix metalloproteinases-2 and -9 and vascular smooth muscle cells of distinct phenotype // Patologicheskaya Fiziologiya i Eksperimental’naya Terapiya (Pathological physiology and experimental therapy). 2020. VOL. 64. № 4. PP. 20–30.
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Section
Original research
