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  • Review Article
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Vascular smooth muscle cells in atherosclerosis

Abstract

Vascular smooth muscle cells (VSMCs) are a major cell type present at all stages of an atherosclerotic plaque. According to the ‘response to injury’ and ‘vulnerable plaque’ hypotheses, contractile VSMCs recruited from the media undergo phenotypic conversion to proliferative synthetic cells that generate extracellular matrix to form the fibrous cap and hence stabilize plaques. However, lineage-tracing studies have highlighted flaws in the interpretation of former studies, revealing that these studies had underestimated both the content and functions of VSMCs in plaques and have thus challenged our view on the role of VSMCs in atherosclerosis. VSMCs are more plastic than previously recognized and can adopt alternative phenotypes, including phenotypes resembling foam cells, macrophages, mesenchymal stem cells and osteochondrogenic cells, which could contribute both positively and negatively to disease progression. In this Review, we present the evidence for VSMC plasticity and summarize the roles of VSMCs and VSMC-derived cells in atherosclerotic plaque development and progression. Correct attribution and spatiotemporal resolution of clinically beneficial and detrimental processes will underpin the success of any therapeutic intervention aimed at VSMCs and their derivatives.

Key points

  • Vascular smooth muscle cells (VSMCs) and VSMC-derived cells are a major source of plaque cells and extracellular matrix at all stages of atherosclerosis.

  • VSMCs contribute to many different plaque cell phenotypes, including extracellular-matrix-producing cells of the fibrous cap, macrophage-like cells, foam cells, mesenchymal stem-cell-like cells and osteochondrogenic cells.

  • Progress has been made in identifying the source of VSMCs and VSMC-derived cells in atherosclerotic plaques, highlighting the importance of the developmental origin, clonal expansion and phenotype switching of VSMCs in atherosclerosis.

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Fig. 1: Overview of the role of VSMCs in atherosclerosis.
Fig. 2: VSMCs in early atherosclerosis.
Fig. 3: VSMCs in late atherosclerosis.
Fig. 4: VSMCs in clinical sequelae of atherosclerosis.

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References

  1. World Health Organization. The top 10 causes of death. WHO https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death (2018).

  2. Pease, D. C. & Paule, W. J. Electron microscopy of elastic arteries; the thoracic aorta of the rat. J. Ultrastruct. Res. 3, 469–483 (1960).

    CAS  PubMed  Google Scholar 

  3. Parker, F. An electron microscopic study of experimental atherosclerosis. Am. J. Pathol. 36, 19–53 (1960).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Geer, J. C., McGill, H. C. J. & Strong, J. P. The fine structure of human atherosclerotic lesions. Am. J. Pathol. 38, 263–287 (1961).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Imai, H. et al. Atherosclerosis in rabbits. Architectural and subcellular alterations of smooth muscle cells of aortas in response to hyperlipemia. Exp. Mol. Pathol. 5, 273–310 (1966).

    CAS  PubMed  Google Scholar 

  6. Chamley, J. H., Groschel-Stewart, U., Campbell, G. R. & Burnstock, G. Distinction between smooth muscle, fibroblasts and endothelial cells in culture by the use of fluoresceinated antibodies against smooth muscle actin. Cell Tissue Res. 177, 445–457 (1977).

    CAS  PubMed  Google Scholar 

  7. Gown, A. M., Vogel, A. M., Gordon, D. & Lu, P. L. A smooth muscle-specific monoclonal antibody recognizes smooth muscle actin isozymes. J. Cell Biol. 100, 807–813 (1985).

    CAS  PubMed  Google Scholar 

  8. Skalli, O. et al. A monoclonal antibody against alpha-smooth muscle actin: a new probe for smooth muscle differentiation. J. Cell Biol. 103, 2787–2796 (1986).

    CAS  PubMed  Google Scholar 

  9. Tsukada, T., Tippens, D., Gordon, D., Ross, R. & Gown, A. M. HHF35, a muscle-actin-specific monoclonal antibody. I. Immunocytochemical and biochemical characterization. Am. J. Pathol. 126, 51–60 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Shanahan, C. M. & Weissberg, P. L. Smooth muscle cell heterogeneity: patterns of gene expression in vascular smooth muscle cells in vitro and in vivo. Arterioscler. Thromb. Vasc. Biol. 18, 333–338 (1998).

    CAS  PubMed  Google Scholar 

  11. Shankman, L. S. et al. KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat. Med. 21, 628–637 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Raja, C. et al. Promoters to study vascular smooth muscle. Arterioscler. Thromb. Vasc. Biol. 39, 603–612 (2019).

    Google Scholar 

  13. Wirth, A. et al. G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nat. Med. 14, 64–68 (2008).

    CAS  PubMed  Google Scholar 

  14. Kuhbandner, S. et al. Temporally controlled somatic mutagenesis in smooth muscle. Genesis 28, 15–22 (2000).

    CAS  PubMed  Google Scholar 

  15. Holtwick, R. et al. Smooth muscle-selective deletion of guanylyl cyclase-A prevents the acute but not chronic effects of ANP on blood pressure. Proc. Natl Acad. Sci. USA 99, 7142–7147 (2002).

    CAS  PubMed  Google Scholar 

  16. Zhang, J. et al. Generation of an adult smooth muscle cell-targeted Cre recombinase mouse model. Arterioscler. Thromb. Vascular Biol. 26, e23–24 (2006).

    Google Scholar 

  17. Feil, S. et al. Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis. Circ. Res. 115, 662–667 (2014).

    CAS  PubMed  Google Scholar 

  18. Gomez, D., Shankman, L. S., Nguyen, A. T. & Owens, G. K. Detection of histone modifications at specific gene loci in single cells in histological sections. Nat. Methods 10, 171–177 (2013). This paper and those of Feil et al. (2014) and Shankman et al. (2015) are the first lineage-tracing studies of VSMCs in the context of atherosclerosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Albarrán-Juárez, J., Kaur, H., Grimm, M., Offermanns, S. & Wettschureck, N. Lineage tracing of cells involved in atherosclerosis. Atherosclerosis 251, 445–453 (2016).

    PubMed  Google Scholar 

  20. Chappell, J. et al. Extensive proliferation of a subset of differentiated, yet plastic, medial vascular smooth muscle cells contributes to neointimal formation in mouse injury and atherosclerosis models. Circ. Res. 119, 1313–1323 (2016). This article demonstrates that different VSMC phenotypes arise from the same ancestral cell in atherosclerosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cherepanova, O. A. et al. Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nat. Med. 22, 657–665 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Jacobsen, K. et al. Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs. JCI Insight 2, 95890 (2017).

    PubMed  Google Scholar 

  23. Misra, A. et al. Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells. Nat. Commun. 9, 2073 (2018). This article provides evidence that secreted factors affect VSMC clonality in atherosclerosis.

    PubMed  PubMed Central  Google Scholar 

  24. Nemenoff, R. A. et al. SDF-1alpha induction in mature smooth muscle cells by inactivation of PTEN is a critical mediator of exacerbated injury-induced neointima formation. Arterioscler. Thromb. Vasc. Biol. 31, 1300–1308 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Jiang, X., Rowitch, D. H., Soriano, P., McMahon, A. P. & Sucov, H. M. Fate of the mammalian cardiac neural crest. Development 127, 1607–1616 (2000).

    CAS  PubMed  Google Scholar 

  26. Waldo, K. L. et al. Secondary heart field contributes myocardium and smooth muscle to the arterial pole of the developing heart. Dev. Biol. 281, 78–90 (2005).

    CAS  PubMed  Google Scholar 

  27. Passman, J. N. et al. A sonic hedgehog signaling domain in the arterial adventitia supports resident Sca1+ smooth muscle progenitor cells. Proc. Natl Acad. Sci. USA 105, 9349–9354 (2008).

    CAS  PubMed  Google Scholar 

  28. Sawada, H., Rateri, D. L., Moorleghen, J. J., Majesky, M. W. & Daugherty, A. Smooth muscle cells derived from second heart field and cardiac neural crest reside in spatially distinct domains in the media of the ascending aorta - brief report. Arterioscler. Thromb. Vasc. Biol. 37, 1722–1726 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Chang, H. Y. Anatomic demarcation of cells: genes to patterns. Science 326, 1206–1207 (2009).

    CAS  PubMed  Google Scholar 

  30. Pruett, N. D. et al. Changing topographic Hox expression in blood vessels results in regionally distinct vessel wall remodeling. Biol. Open 1, 430–435 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Topouzis, S. & Majesky, M. W. Smooth muscle lineage diversity in the chick embryo. Two types of aortic smooth muscle cell differ in growth and receptor-mediated transcriptional responses to transforming growth factor-beta. Dev. Biol. 178, 430–445 (1996).

    CAS  PubMed  Google Scholar 

  32. Xie, W.-B. B. et al. Smad2 and myocardin-related transcription factor B cooperatively regulate vascular smooth muscle differentiation from neural crest cells. Circ. Res. 113, 76–86 (2013).

    Google Scholar 

  33. Madura, J. A. 2nd et al. Regional differences in platelet-derived growth factor production by the canine aorta. J. Vasc. Res. 33, 53–61 (1996).

    CAS  PubMed  Google Scholar 

  34. Oh, J., Richardson, J. A. & Olson, E. N. Requirement of myocardin-related transcription factor-B for remodeling of branchial arch arteries and smooth muscle differentiation. Proc. Natl Acad. Sci. USA 102, 15122–15127 (2005).

    CAS  PubMed  Google Scholar 

  35. Li, J. et al. Myocardin-related transcription factor B is required in cardiac neural crest for smooth muscle differentiation and cardiovascular development. Proc. Natl Acad. Sci. USA 102, 8916–8921 (2005).

    CAS  PubMed  Google Scholar 

  36. Trigueros-Motos, L. et al. Embryological-origin-dependent differences in homeobox expression in adult aorta: role in regional phenotypic variability and regulation of NF-kappaB activity. Arterioscler. Thromb. Vasc. Biol. 33, 1248–1256 (2013).

    CAS  PubMed  Google Scholar 

  37. Owens, A. P. 3rd et al. Angiotensin II induces a region-specific hyperplasia of the ascending aorta through regulation of inhibitor of differentiation 3. Circ. Res. 106, 611–619 (2010).

    CAS  PubMed  Google Scholar 

  38. Bentzon, J. F., Sondergaard, C. S., Kassem, M. & Falk, E. Smooth muscle cells healing atherosclerotic plaque disruptions are of local, not blood, origin in apolipoprotein E knockout mice. Circulation 116, 2053–2061 (2007).

    CAS  PubMed  Google Scholar 

  39. Bentzon, J. F. et al. Smooth muscle cells in atherosclerosis originate from the local vessel wall and not circulating progenitor cells in ApoE knockout mice. Arterioscler. Thromb. Vasc. Biol. 26, 2696–2702 (2006).

    CAS  PubMed  Google Scholar 

  40. Yu, H. et al. Bone marrow–derived smooth muscle–like cells are infrequent in advanced primary atherosclerotic plaques but promote atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 31, 1291–1299 (2011).

    CAS  PubMed  Google Scholar 

  41. Sata, M. et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat. Med. 8, 403–409 (2002).

    CAS  PubMed  Google Scholar 

  42. Caplice, N. M. et al. Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation. Proc. Natl Acad. Sci. USA 100, 4754–4759 (2003).

    CAS  PubMed  Google Scholar 

  43. Dobnikar, L. et al. Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels. Nat. Commun. 9, 4567 (2018).

    PubMed  PubMed Central  Google Scholar 

  44. Majesky, M. W. Developmental basis of vascular smooth muscle diversity. Arterioscler. Thromb. Vasc. Biol. 27, 1248–1258 (2007).

    CAS  PubMed  Google Scholar 

  45. Haimovici, H. The role of arterial tissue susceptibility in atherogenesis. Texas Heart Inst. J. 18, 81–83 (1991).

    CAS  Google Scholar 

  46. Benditt, E. P. & Benditt, J. M. Evidence for a monoclonal origin of human atherosclerotic plaques. Proc. Natl Acad. Sci. USA 70, 1753–1756 (1973).

    CAS  PubMed  Google Scholar 

  47. Murry, C. E., Gipaya, C. T., Bartosek, T., Benditt, E. P. & Schwartz, S. M. Monoclonality of smooth muscle cells in human atherosclerosis. Am. J. Pathol. 151, 697–705 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Chung, I. M., Schwartz, S. M. & Murry, C. E. Clonal architecture of normal and atherosclerotic aorta: implications for atherogenesis and vascular development. Am. J. Pathol. 152, 913–923 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Cheung, C., Bernardo, A. S., Trotter, M. W. B., Pedersen, R. A. & Sinha, S. Generation of human vascular smooth muscle subtypes provides insight into embryological origin–dependent disease susceptibility. Nat. Biotechnol. 30, 165–173 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sinha, S. & Santoro, M. M. New models to study vascular mural cell embryonic origin: implications in vascular diseases. Cardiovasc. Res. 114, 481–491 (2018).

    CAS  PubMed  Google Scholar 

  51. Clarke, M. C. H. et al. Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcification and medial degeneration. Circ. Res. 102, 1529–1538 (2008).

    CAS  PubMed  Google Scholar 

  52. Lee, S. H., Hungerford, J. E., Little, C. D. & Iruela-Arispe, M. L. Proliferation and differentiation of smooth muscle cell precursors occurs simultaneously during the development of the vessel wall. Dev. Dyn. 209, 342–352 (1997).

    CAS  PubMed  Google Scholar 

  53. Poole, J. C., Cromwell, S. B. & Benditt, E. P. Behavior of smooth muscle cells and formation of extracellular structures in the reaction of arterial walls to injury. Am. J. Pathol. 62, 391–414 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Kocher, O. et al. Phenotypic features of smooth muscle cells during the evolution of experimental carotid artery intimal thickening. Biochemical and morphologic studies. Lab. Invest. 65, 459–470 (1991).

    CAS  PubMed  Google Scholar 

  55. Rong, J. X., Shapiro, M., Trogan, E. & Fisher, E. A. Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proc. Natl Acad. Sci. USA 100, 13531–13536 (2003).

    CAS  PubMed  Google Scholar 

  56. Chamley-Campbell, J., Campbell, G. R. & Ross, R. The smooth muscle cell in culture. Physiol. Rev. 59, 1–61 (1979).

    CAS  PubMed  Google Scholar 

  57. Kaur, H. et al. Single-cell profiling reveals heterogeneity and functional patterning of GPCR expression in the vascular system. Nat. Commun. 8, 15700 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Pipes, G. C. T., Creemers, E. E. & Olson, E. N. The myocardin family of transcriptional coactivators: versatile regulators of cell growth, migration, and myogenesis. Genes Dev. 20, 1545–1556 (2006).

    CAS  PubMed  Google Scholar 

  59. Vengrenyuk, Y. et al. Cholesterol loading reprograms the microRNA-143/145-myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype. Arterioscler. Thromb. Vasc. Biol. 35, 535–546 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 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 129, 1551–1559 (2014).

    CAS  PubMed  Google Scholar 

  61. Andreeva, E. R., Pugach, I. M. & Orekhov, A. N. Subendothelial smooth muscle cells of human aorta express macrophage antigen in situ and in vitro. Atherosclerosis 135, 19–27 (1997).

    CAS  PubMed  Google Scholar 

  62. Wissler, R. W. The arterial medial cell, smooth muscle, or multifunctional mesenchyme? Circulation 36, 1–4 (1967).

    CAS  PubMed  Google Scholar 

  63. Alves, R. D. A. M., Eijken, M., van de Peppel, J. & van Leeuwen, J. P. T. M. Calcifying vascular smooth muscle cells and osteoblasts: independent cell types exhibiting extracellular matrix and biomineralization-related mimicries. BMC Genomics 15, 965 (2014).

    PubMed  PubMed Central  Google Scholar 

  64. 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. 114, 590–600 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Sheikh, A. Q., Misra, A., Rosas, I. O., Adams, R. H. & Greif, D. M. Smooth muscle cell progenitors are primed to muscularize in pulmonary hypertension. Sci. Transl Med. 7, 308ra159 (2015).

    PubMed  PubMed Central  Google Scholar 

  66. Sheikh, A. Q., Saddouk, F. Z., Ntokou, A., Mazurek, R. & Greif, D. M. Cell autonomous and non-cell autonomous regulation of SMC progenitors in pulmonary hypertension. Cell Rep. 23, 1152–1165 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Herring, B. P., Hoggatt, A. M., Burlak, C. & Offermanns, S. Previously differentiated medial vascular smooth muscle cells contribute to neointima formation following vascular injury. Vasc. Cell 6, 21 (2014).

    PubMed  PubMed Central  Google Scholar 

  68. Gomez, D. & Owens, G. K. Reconciling smooth muscle cell oligoclonality and proliferative capacity in experimental atherosclerosis. Circ. Res. 119, 1262–1264 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhang, L. & Vijg, J. Somatic mutagenesis in mammals and its implications for human disease and aging. Annu. Rev. Genet. 52, 397–419 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111–121 (2017).

    PubMed  PubMed Central  Google Scholar 

  71. Martin, G. M. & Sprague, C. A. Clonal senescence and atherosclerosis. Lancet 2, 1370–1371 (1972).

    CAS  PubMed  Google Scholar 

  72. Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014).

    CAS  PubMed  Google Scholar 

  73. Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).

    CAS  PubMed  Google Scholar 

  74. Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev. 24, 2463–2479 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Grootaert, M. O. et al. Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis. Autophagy 11, 2014–2032 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Matthews, C. et al. Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stress. Circ. Res. 99, 156–164 (2006).

    CAS  PubMed  Google Scholar 

  77. Coppe, J.-P., Desprez, P.-Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Coppé, J.-P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLOS Biol. 6, e301 (2008).

    PubMed Central  Google Scholar 

  79. Orjalo, A. V., Bhaumik, D., Gengler, B. K., Scott, G. K. & Campisi, J. Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc. Natl Acad. Sci. USA 106, 17031–17036 (2009).

    CAS  PubMed  Google Scholar 

  80. Gardner, S. E., Humphry, M., Bennett, M. R. & Clarke, M. C. H. Senescent vascular smooth muscle cells drive inflammation through an interleukin-1α-dependent senescence-associated secretory phenotype. Arterioscler. Thromb. Vasc. Biol. 35, 1963–1974 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Kang, C. et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 349, aaa5612 (2015).

    PubMed  PubMed Central  Google Scholar 

  82. Laberge, R.-M. et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol. 17, 1049–1061 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Kang, T.-W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).

    CAS  PubMed  Google Scholar 

  84. Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016). This article demonstrates the effect of senescence in atherosclerosis.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Coppé, J.-P. et al. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLOS ONE 5, e9188 (2010).

    PubMed  PubMed Central  Google Scholar 

  86. Wang, J. et al. Vascular smooth muscle cell senescence promotes atherosclerosis and features of plaque vulnerability. Circulation 132, 1909–1919 (2015).

    CAS  PubMed  Google Scholar 

  87. Shah, A. et al. Defective base excision repair of oxidative DNA damage in vascular smooth muscle cells promotes atherosclerosis. Circulation 138, 1446–1462 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Virmani, R., Kolodgie, F. D., Burke, A. P., Farb, A. & Schwartz, S. M. Lessons from sudden coronary death. Arterioscler. Thromb. Vasc. Biol. 20, 1262–1275 (2000).

    CAS  PubMed  Google Scholar 

  89. Yahagi, K. et al. Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat. Rev. Cardiol. 13, 79–98 (2016).

    CAS  PubMed  Google Scholar 

  90. Velican, C. & Velican, D. Intimal thickening in developing coronary arteries and its relevance to atherosclerotic involvement. Atherosclerosis 23, 345–355 (1976).

    Google Scholar 

  91. Ikari, Y., McManus, B. M., Kenyon, J. & Schwartz, S. M. Neonatal intima formation in the human coronary artery. Arterioscler. Thromb. Vasc. Biol. 19, 2036–2040 (1999).

    CAS  PubMed  Google Scholar 

  92. Stary, H. C. et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. Arterioscler. Thromb. 14, 840–857 (1994).

    CAS  PubMed  Google Scholar 

  93. Velican, C. A dissecting view on the role of the fatty streak in the pathogenesis of human atherosclerosis: culprit or bystander? Med. Interne 19, 321–337 (1981).

    CAS  PubMed  Google Scholar 

  94. Armstrong, M. L., Heistad, D. D., Megan, M. B., Lopez, J. A. & Harrison, D. G. Reversibility of atherosclerosis. Cardiovasc. Clin. 20, 113–126 (1990).

    CAS  PubMed  Google Scholar 

  95. Strong, J. P. et al. Prevalence and extent of atherosclerosis in adolescents and young adults: implications for prevention from the Pathobiological Determinants of Atherosclerosis in Youth Study. JAMA 281, 727–735 (1999).

    CAS  PubMed  Google Scholar 

  96. Nakashima, Y., Chen, Y.-X., Kinukawa, N. & Sueishi, K. Distributions of diffuse intimal thickening in human arteries: preferential expression in atherosclerosis-prone arteries from an early age. Virchows Arch. 441, 279–288 (2002).

    PubMed  Google Scholar 

  97. Nakashima, Y., Wight, T. N. & Sueishi, K. Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans. Cardiovasc. Res. 79, 14–23 (2008).

    CAS  PubMed  Google Scholar 

  98. Mosse, P. R., Campbell, G. R., Wang, Z. L. & Campbell, J. H. Smooth muscle phenotypic expression in human carotid arteries. I. Comparison of cells from diffuse intimal thickenings adjacent to atheromatous plaques with those of the media. Lab. Invest. 53, 556–562 (1985).

    CAS  PubMed  Google Scholar 

  99. Aikawa, M. et al. Human smooth muscle myosin heavy chain isoforms as molecular markers for vascular development and atherosclerosis. Circ. Res. 73, 1000–1012 (1993).

    CAS  PubMed  Google Scholar 

  100. Andreeva, E. R., Pugach, I. M. & Orekhov, A. N. Collagen-synthesizing cells in initial and advanced atherosclerotic lesions of human aorta. Atherosclerosis 130, 133–142 (1997).

    CAS  PubMed  Google Scholar 

  101. Skalen, K. et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417, 750–754 (2002).

    CAS  PubMed  Google Scholar 

  102. Campbell, J. H., Popadynec, L., Nestel, P. J. & Campbell, G. R. Lipid accumulation in arterial smooth muscle cells. Influence of phenotype. Atherosclerosis 47, 279–295 (1983).

    CAS  PubMed  Google Scholar 

  103. Campbell, J. H., Reardon, M. F., Campbell, G. R. & Nestel, P. J. Metabolism of atherogenic lipoproteins by smooth muscle cells of different phenotype in culture. Arteriosclerosis 5, 318–328 (1985).

    CAS  PubMed  Google Scholar 

  104. Kim, D. N., Imai, H., Schmee, J., Lee, K. T. & Thomas, W. A. Intimal cell mass-derived atherosclerotic lesions in the abdominal aorta of hyperlipidemic swine. Part 1. Cell of origin, cell divisions and cell losses in first 90 days on diet. Atherosclerosis 56, 169–188 (1985).

    CAS  PubMed  Google Scholar 

  105. Ang, A. H., Tachas, G., Campbell, J. H., Bateman, J. F. & Campbell, G. R. Collagen synthesis by cultured rabbit aortic smooth-muscle cells. Alteration with phenotype. Biochem. J. 265, 461–469 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Lee, R. T. et al. Mechanical strain induces specific changes in the synthesis and organization of proteoglycans by vascular smooth muscle cells. J. Biol. Chem. 276, 13847–13851 (2001).

    CAS  PubMed  Google Scholar 

  107. Little, P. J., Tannock, L., Olin, K. L., Chait, A. & Wight, T. N. Proteoglycans synthesized by arterial smooth muscle cells in the presence of transforming growth factor-beta1 exhibit increased binding to LDLs. Arterioscler. Thromb. Vasc. Biol. 22, 55–60 (2002).

    CAS  PubMed  Google Scholar 

  108. Chang, M. Y., Potter-Perigo, S., Tsoi, C., Chait, A. & Wight, T. N. Oxidized low density lipoproteins regulate synthesis of monkey aortic smooth muscle cell proteoglycans that have enhanced native low density lipoprotein binding properties. J. Biol. Chem. 275, 4766–4773 (2000).

    CAS  PubMed  Google Scholar 

  109. S. R., L. et al. Extracellular matrix proteomics identifies molecular signature of symptomatic carotid plaques. J. Clin. Invest. 127, 1546–1560 (2017).

    Google Scholar 

  110. Tran-Lundmark, K. et al. Heparan sulfate in perlecan promotes mouse atherosclerosis: roles in lipid permeability, lipid retention, and smooth muscle cell proliferation. Circ. Res. 103, 43–52 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Smith, E. B. & Slater, R. S. The microdissection of large atherosclerotic plaques to give morphologically and topographically defined fractions for analysis. 1. The lipids in the isolated fractions. Atherosclerosis 15, 37–56 (1972).

    CAS  PubMed  Google Scholar 

  112. Tabas, I., Williams, K. J. & Borén, J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: Update and therapeutic implications. Circulation 116, 1832–1844 (2007).

    CAS  PubMed  Google Scholar 

  113. Williams, K. J. & Tabas, I. The response-to-retention hypothesis of early atherogenesis. Arterioscler. Thromb. Vasc. Biol. 15, 551–561 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Thompson, J. C., Tang, T., Wilson, P. G., Yoder, M. H. & Tannock, L. R. Increased atherosclerosis in mice with increased vascular biglycan content. Atherosclerosis 235, 71–75 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Napoli, C. et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J. Clin. Invest. 100, 2680–2690 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Nakagawa, K. & Nakashima, Y. Pathologic intimal thickening in human atherosclerosis is formed by extracellular accumulation of plasma-derived lipids and dispersion of intimal smooth muscle cells. Atherosclerosis 274, 235–242 (2018).

    CAS  PubMed  Google Scholar 

  117. Kockx, M. M. et al. Apoptosis and related proteins in different stages of human atherosclerotic plaques. Circulation 97, 2307–2315 (1998).

    CAS  PubMed  Google Scholar 

  118. Okura, Y. et al. Oxidized low-density lipoprotein is associated with apoptosis of vascular smooth muscle cells in human atherosclerotic plaques. Circulation 102, 2680–2686 (2000).

    CAS  PubMed  Google Scholar 

  119. Tulenko, T. N., Chen, M., Mason, P. E. & Mason, R. P. Physical effects of cholesterol on arterial smooth muscle membranes: evidence of immiscible cholesterol domains and alterations in bilayer width during atherogenesis. J. Lipid Res. 39, 947–956 (1998).

    CAS  PubMed  Google Scholar 

  120. Robbins, C. S. et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat. Med. 19, 1166–1172 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Ensan, S. et al. Self-renewing resident arterial macrophages arise from embryonic CX3CR1+ precursors and circulating monocytes immediately after birth. Nat. Immunol. 17, 159–168 (2016).

    CAS  PubMed  Google Scholar 

  122. Nahrendorf, M. Myeloid cell contributions to cardiovascular health and disease. Nat. Med. 24, 711–720 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Berliner, J. A. et al. Minimally modified low density lipoprotein stimulates monocyte endothelial interactions. J. Clin. Invest. 85, 1260–1266 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Nelken, N. A., Coughlin, S. R., Gordon, D. & Wilcox, J. N. Monocyte chemoattractant protein-1 in human atheromatous plaques. J. Clin. Invest. 88, 1121–1127 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Cushing, S. D. et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc. Natl Acad. Sci. USA 87, 5134–5138 (1990).

    CAS  PubMed  Google Scholar 

  126. Quinn, M. T., Parthasarathy, S., Fong, L. G. & Steinberg, D. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc. Natl Acad. Sci. USA 84, 2995–2998 (1987).

    CAS  PubMed  Google Scholar 

  127. Qiao, J. H. et al. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am. J. Pathol. 150, 1687–1699 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Swirski, F. K. et al. Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc. Natl Acad. Sci. USA 103, 10340–10345 (2006).

    CAS  PubMed  Google Scholar 

  129. Ross, R. et al. Localization of PDGF-B protein in macrophages in all phases of atherogenesis. Science 248, 1009–1012 (1990).

    CAS  PubMed  Google Scholar 

  130. Campbell, J. H., Rennick, R. E., Kalevitch, S. G. & Campbell, G. R. Heparan sulfate-degrading enzymes induce modulation of smooth muscle phenotype. Exp. Cell Res. 200, 156–167 (1992).

    CAS  PubMed  Google Scholar 

  131. Ait-Oufella, H. et al. Defective mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 28, 1429–1431 (2008).

    CAS  PubMed  Google Scholar 

  132. Ait-Oufella, H. et al. Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice. Circulation 115, 2168–2177 (2007).

    CAS  PubMed  Google Scholar 

  133. Clarke, M. C. H. H., Talib, S., Figg, N. L. & Bennett, M. R. Vascular smooth muscle cell apoptosis induces interleukin-1-directed inflammation: effects of hyperlipidemia-mediated inhibition of phagocytosis. Circ. Res. 106, 363–372 (2010).

    CAS  PubMed  Google Scholar 

  134. Shaw, P. X. et al. Human-derived anti-oxidized LDL autoantibody blocks uptake of oxidized LDL by macrophages and localizes to atherosclerotic lesions in vivo. Arterioscler. Thromb. Vasc. Biol. 21, 1333–1339 (2001).

    CAS  PubMed  Google Scholar 

  135. Schrijvers, D. M., De Meyer, G. R. Y., Kockx, M. M., Herman, A. G. & Martinet, W. Phagocytosis of apoptotic cells by macrophages is impaired in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 25, 1256–1261 (2005).

    CAS  PubMed  Google Scholar 

  136. Li, S. et al. Defective phagocytosis of apoptotic cells by macrophages in atherosclerotic lesions of ob/ob mice and reversal by a fish oil diet. Circ. Res. 105, 1072–1082 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Bäck, M., Yurdagul, A., Tabas, I., Öörni, K. & Kovanen, P. T. Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-019-0169-2 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Naik, V. et al. Sources of cells that contribute to atherosclerotic intimal calcification: An in vivo genetic fate mapping study. Cardiovasc. Res 94, 545–554 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Sano, H. et al. Functional blockade of platelet-derived growth factor receptor-beta but not of receptor-alpha prevents vascular smooth muscle cell accumulation in fibrous cap lesions in apolipoprotein E-deficient mice. Circulation 103, 2955–2960 (2001).

    CAS  PubMed  Google Scholar 

  140. Rekhter, M. D. et al. Type I collagen gene expression in human atherosclerosis. Localization to specific plaque regions. Am. J. Pathol. 143, 1634–1648 (1993).

    CAS  PubMed  Google Scholar 

  141. Gomez, D. et al. Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice. Nat. Med. 24, 1418–1429 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Davies, M. J., Richardson, P. D., Woolf, N., Katz, D. R. & Mann, J. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br. Heart J. 69, 377–381 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Durgin, B. G. et al. Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions. Am. J. Physiol. Heart Circ. Physiol. 312, H943–H958 (2017).

    PubMed  PubMed Central  Google Scholar 

  144. Amento, E. P., Ehsani, N., Palmer, H. & Libby, P. Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arterioscler. Thromb. Vasc. Biol. 11, 1223–1230 (1991).

    CAS  Google Scholar 

  145. Rekhter, M. D. Collagen synthesis in atherosclerosis: too much and not enough. Cardiovasc. Res. 41, 376–384 (1999).

    CAS  PubMed  Google Scholar 

  146. Wang, Y. et al. Smooth muscle cells contribute the majority of foam cells in ApoE (apolipoprotein E)-deficient mouse atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 39, 876–887 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. New, S. E. P. et al. Macrophage-derived matrix vesicles: an alternative novel mechanism for microcalcification in atherosclerotic plaques. Circ. Res. 113, 72–77 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Kapustin, A. N. et al. Vascular smooth muscle cell calcification is mediated by regulated exosome secretion. Circ. Res. 116, 1312–1323 (2015).

    CAS  PubMed  Google Scholar 

  149. Hutcheson, J. D. et al. Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques. Nat. Mater. 15, 335–343 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Proudfoot, D. et al. Apoptosis regulates human vascular calcification in vitro: evidence for initiation of vascular calcification by apoptotic bodies. Circ. Res. 87, 1055–1062 (2000).

    CAS  PubMed  Google Scholar 

  151. Rattazzi, M. et al. Calcification of advanced atherosclerotic lesions in the innominate arteries of ApoE-deficient mice: potential role of chondrocyte-like cells. Arterioscler. Thromb. Vasc. Biol. 25, 1420–1425 (2005).

    CAS  PubMed  Google Scholar 

  152. Leroux-Berger, M. et al. Pathologic calcification of adult vascular smooth muscle cells differs on their crest or mesodermal embryonic origin. J. Bone Miner. Res. 26, 1543–1553 (2011).

    CAS  PubMed  Google Scholar 

  153. Espitia, O. et al. Implication of molecular vascular smooth muscle cell heterogeneity among arterial beds in arterial calcification. PLOS ONE 13, e0191976 (2018).

    PubMed  PubMed Central  Google Scholar 

  154. Proudfoot, D., Skepper, J. N., Shanahan, C. M. & Weissberg, P. L. Calcification of human vascular cells in vitro is correlated with high levels of matrix Gla protein and low levels of osteopontin expression. Arterioscler. Thromb. Vasc. Biol. 18, 379–388 (1998).

    CAS  PubMed  Google Scholar 

  155. Steitz, S. A. et al. Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ. Res. 89, 1147–1154 (2001).

    CAS  PubMed  Google Scholar 

  156. Farrokhi, E., Samani, K. G. & Chaleshtori, M. H. Oxidized low-density lipoprotein increases bone sialoprotein expression in vascular smooth muscle cells via runt-related transcription factor 2. Am. J. Med. Sci. 349, 240–243 (2015).

    PubMed  Google Scholar 

  157. Al-Aly, Z. et al. Aortic Msx2-Wnt calcification cascade is regulated by TNF-alpha-dependent signals in diabetic Ldlr−/− mice. Arterioscler. Thromb. Vasc. Biol. 27, 2589–2596 (2007).

    CAS  PubMed  Google Scholar 

  158. Ceneri, N. et al. Rac2 modulates atherosclerotic calcification by regulating macrophage interleukin-1β production. Arterioscler. Thromb. Vasc. Biol. 37, 328–340 (2017).

    CAS  PubMed  Google Scholar 

  159. Zhang, K. et al. Interleukin-18 enhances vascular calcification and osteogenic differentiation of vascular smooth muscle cells through TRPM7 activation. Arterioscler. Thromb. Vasc. Biol. 37, 1933–1943 (2017).

    CAS  PubMed  Google Scholar 

  160. Cheng, S.-L. et al. Targeted reduction of vascular Msx1 and Msx2 mitigates arteriosclerotic calcification and aortic stiffness in LDLR-deficient mice fed diabetogenic diets. Diabetes 63, 4326–4337 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Hofmann Bowman, M. A. et al. S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein E-null mice by activating an osteogenic gene regulatory program. Arterioscler. Thromb. Vasc. Biol. 31, 337–344 (2011).

    CAS  PubMed  Google Scholar 

  162. Nakagawa, Y. et al. Paracrine osteogenic signals via bone morphogenetic protein-2 accelerate the atherosclerotic intimal calcification in vivo. Arterioscler. Thromb. Vasc. Biol. 30, 1908–1915 (2010).

    CAS  PubMed  Google Scholar 

  163. Davies, M. J. & Thomas, A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N. Engl. J. Med. 310, 1137–1140 (1984).

    CAS  PubMed  Google Scholar 

  164. Pasterkamp, G., Den Ruijter, H. M. & Libby, P. Temporal shifts in clinical presentation and underlying mechanisms of atherosclerotic disease. Nat. Rev. Cardiol. 14, 21–29 (2016).

    PubMed  Google Scholar 

  165. Newby, A. C. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol. Rev. 85, 1–31 (2005).

    CAS  PubMed  Google Scholar 

  166. Sukhova, G. K. et al. Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques. Circulation 99, 2503–2509 (1999).

    CAS  PubMed  Google Scholar 

  167. Yu, H. et al. FOXO3a (forkhead transcription factor O subfamily member 3a) links vascular smooth muscle cell apoptosis, matrix breakdown, atherosclerosis, and vascular remodeling through a novel pathway involving MMP13 (matrix metalloproteinase 13). Arterioscler. Thromb. Vasc. Biol. 38, 555–565 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Falk, E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br. Heart J. 50, 127–134 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. van der Wal, A. C., Becker, A. E., van der Loos, C. M. & Das, P. K. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 89, 36–44 (1994).

    PubMed  Google Scholar 

  170. Gijsen, F., van der Giessen, A., van der Steen, A. & Wentzel, J. Shear stress and advanced atherosclerosis in human coronary arteries. J. Biomech. 46, 240–247 (2013).

    PubMed  Google Scholar 

  171. Vengrenyuk, Y. et al. A hypothesis for vulnerable plaque rupture due to stress-induced debonding around cellular microcalcifications in thin fibrous caps. Proc. Natl Acad. Sci. USA 103, 14678–14683 (2006).

    CAS  PubMed  Google Scholar 

  172. Gordon, D., Reidy, M. A., Benditt, E. P. & Schwartz, S. M. Cell proliferation in human coronary arteries. Proc. Natl Acad. Sci. USA 87, 4600–4604 (1990).

    CAS  PubMed  Google Scholar 

  173. O’Brien, E. R. et al. Proliferation in primary and restenotic coronary atherectomy tissue. Implications for antiproliferative therapy. Circ. Res. 73, 223–231 (1993).

    PubMed  Google Scholar 

  174. Han, D. K. et al. Evidence for apoptosis in human atherogenesis and in a rat vascular injury model. Am. J. Pathol. 147, 267–277 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Geng, Y. J. & Libby, P. Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1 beta-converting enzyme. Am. J. Pathol. 147, 251–266 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Isner, J. M., Kearney, M., Bortman, S. & Passeri, J. Apoptosis in human atherosclerosis and restenosis. Circulation 91, 2703–2711 (1995).

    CAS  PubMed  Google Scholar 

  177. Bauriedel, G. et al. Role of smooth muscle cell death in advanced coronary primary lesions: implications for plaque instability. Cardiovasc. Res. 41, 480–488 (1999).

    CAS  PubMed  Google Scholar 

  178. Clarke, M. C. H. et al. Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nat. Med. 12, 1075–1080 (2006).

    CAS  PubMed  Google Scholar 

  179. Bennett, M. R., Evan, G. I. & Schwartz, S. M. Apoptosis of human vascular smooth muscle cells derived from normal vessels and coronary atherosclerotic plaques. J. Clin. Invest. 95, 2266–2274 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Patel, V. A. et al. Defect in insulin-like growth factor-1 survival mechanism in atherosclerotic plaque-derived vascular smooth muscle cells is mediated by reduced surface binding and signaling. Circ. Res. 88, 895–902 (2001).

    CAS  PubMed  Google Scholar 

  181. Lyon, C. A., Johnson, J. L., Williams, H., Sala-Newby, G. B. & George, S. J. Soluble N-cadherin overexpression reduces features of atherosclerotic plaque instability. Arterioscler. Thromb. Vasc. Biol. 29, 195–201 (2009).

    CAS  PubMed  Google Scholar 

  182. von der Thusen, J. H. et al. Induction of atherosclerotic plaque rupture in apolipoprotein E-/- mice after adenovirus-mediated transfer of p53. Circulation 105, 2064–2070 (2002).

    PubMed  Google Scholar 

  183. Fernandez-Hernando, C., Jozsef, L., Jenkins, D., Di Lorenzo, A. & Sessa, W. C. Absence of Akt1 reduces vascular smooth muscle cell migration and survival and induces features of plaque vulnerability and cardiac dysfunction during atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 29, 2033–2040 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. von der Thüsen, J. H. et al. IGF-1 has plaque-stabilizing effects in atherosclerosis by altering vascular smooth muscle cell phenotype. Am. J. Pathol. 178, 924–934 (2011).

    PubMed  PubMed Central  Google Scholar 

  185. Gorenne, I. et al. Vascular smooth muscle cell sirtuin 1 protects against DNA damage and inhibits atherosclerosis. Circulation 127, 386–396 (2013).

    CAS  PubMed  Google Scholar 

  186. Tucka, J. et al. Akt1 regulates vascular smooth muscle cell apoptosis through FoxO3a and Apaf1 and protects against arterial remodeling and atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 34, 2421–2428 (2014).

    CAS  PubMed  Google Scholar 

  187. Rotllan, N. et al. Genetic evidence supports a major role for Akt1 in VSMCs during atherogenesis. Circ. Res. 116, 1744–1752 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Osonoi, Y. et al. Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis. Autophagy 14, 1991–2006 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Zheng, Y., Humphry, M., Maguire, J. J., Bennett, M. R. & Clarke, M. C. H. Intracellular interleukin-1 receptor 2 binding prevents cleavage and activity of interleukin-1alpha, controlling necrosis-induced sterile inflammation. Immunity 38, 285–295 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Alloza, I. et al. RNAseq based transcriptomics study of SMCs from carotid atherosclerotic plaque: BMP2 and IDs proteins are crucial regulators of plaque stability. Sci. Rep. 7, 3470 (2017).

    PubMed  PubMed Central  Google Scholar 

  191. Gorenne, I., Kavurma, M., Scott, S. & Bennett, M. Vascular smooth muscle cell senescence in atherosclerosis. Cardiovasc. Res. 72, 9–17 (2006).

    CAS  PubMed  Google Scholar 

  192. Liu, Y., Drozdov, I., Shroff, R., Beltran, L. E. & Shanahan, C. M. Prelamin A accelerates vascular calcification via activation of the DNA damage response and senescence-associated secretory phenotype in vascular smooth muscle cells. Circ. Res. 112, e99–109 (2013).

    CAS  PubMed  Google Scholar 

  193. Kolodgie, F. D. et al. Differential accumulation of proteoglycans and hyaluronan in culprit lesions: insights into plaque erosion. Arterioscler. Thromb. Vasc. Biol. 22, 1642–1648 (2002).

    CAS  PubMed  Google Scholar 

  194. Franck, G. et al. Flow perturbation mediates neutrophil recruitment and potentiates endothelial injury via TLR2 in mice: implications for superficial erosion. Circ. Res. 121, 31–42 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Tricot, O. et al. Relation between endothelial cell apoptosis and blood flow direction in human atherosclerotic plaques. Circulation 101, 2450–2453 (2000).

    CAS  PubMed  Google Scholar 

  196. Papakonstantinou, E., Karakiulakis, G., Roth, M. & Block, L. H. Platelet-derived growth factor stimulates the secretion of hyaluronic acid by proliferating human vascular smooth muscle cells. Proc. Natl Acad. Sci. USA 92, 9881–9885 (1995).

    CAS  PubMed  Google Scholar 

  197. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    CAS  PubMed  Google Scholar 

  198. van der Harst, P. & Verweij, N. Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ. Res. 122, 433–443 (2018).

    PubMed  PubMed Central  Google Scholar 

  199. Miller, C. L. et al. Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci. Nat. Commun. 7, 12092 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Liu, B. et al. Genetic regulatory mechanisms of smooth muscle cells map to coronary artery disease risk loci. Am. J. Hum. Genet. 103, 377–388 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Lo Sardo, V. et al. Unveiling the role of the most impactful cardiovascular risk locus through haplotype editing. Cell 175, 1796–1810 (2018).

    CAS  PubMed  Google Scholar 

  202. Iyer, D. et al. Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk. PLOS Genet. 14, e1007681 (2018).

    PubMed  PubMed Central  Google Scholar 

  203. Piedrahita, J. A., Zhang, S. H., Hagaman, J. R., Oliver, P. M. & Maeda, N. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc. Natl Acad. Sci. USA 89, 4471–4475 (1992).

    CAS  PubMed  Google Scholar 

  204. Ishibashi, S. et al. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery. J. Clin. Invest. 92, 883–893 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Schwartz, S. M., deBlois, D. & O’Brien, E. R. The intima. Soil for atherosclerosis and restenosis. Circ. Res. 77, 445–465 (1995).

    CAS  PubMed  Google Scholar 

  206. Campbell, G. R. & Campbell, J. H. Smooth muscle phenotypic changes in arterial wall homeostasis: implications for the pathogenesis of atherosclerosis. Exp. Mol. Pathol. 42, 139–162 (1985).

    CAS  PubMed  Google Scholar 

  207. Ross, R. & Glomset, J. A. Atherosclerosis and the arterial smooth muscle cell: proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science 180, 1332–1339 (1973).

    CAS  Google Scholar 

  208. Ross, R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801–809 (1993).

    CAS  PubMed  Google Scholar 

  209. Schwartz, S. M., Virmani, R. & Rosenfeld, M. E. The good smooth muscle cells in atherosclerosis. Curr. Atheroscler. Rep. 2, 422–429 (2000).

    CAS  PubMed  Google Scholar 

  210. Movat, H. Z., Haust, M. D. & More, R. H. The morphologic elements in the early lesions of arteriosclerosis. Am. J. Pathol. 35, 93–101 (1959).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Buck, R. C. The fine structure of the aortic endothelial lesions in experimental cholesterol atherosclerosis of rabbits. Am. J. Pathol. 34, 897–909 (1958).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Wolinsky, H. & Glagov, S. Structural basis for the static mechanical properties of the aortic media. Circ. Res. 14, 400–413 (1964).

    CAS  PubMed  Google Scholar 

  213. Ross, R., Glomset, J. & Harker, L. Response to injury and atherogenesis. Am. J. Pathol. 86, 675–684 (1977).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Davies, M. J. & Thomas, A. C. Plaque fissuring—the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Heart 53, 363–373 (1985).

    CAS  Google Scholar 

  215. Etchevers, H. C., Vincent, C., Le Douarin, N. M. & Couly, G. F. The cephalic neural crest provides pericytes and smooth muscle cells to all blood vessels of the face and forebrain. Development 128, 1059–1068 (2001).

    CAS  PubMed  Google Scholar 

  216. Majesky, M. W., Dong, X. R., Regan, J. N. & Hoglund, V. J. Vascular smooth muscle progenitor cells: building and repairing blood vessels. Circ. Res. 108, 365–377 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Bentzon, J. F. & Majesky, M. W. Lineage tracking of origin and fate of smooth muscle cells in atherosclerosis. Cardiovasc. Res. 114, 492–500 (2018).

    CAS  PubMed  Google Scholar 

  218. Wasteson, P. et al. Developmental origin of smooth muscle cells in the descending aorta in mice. Development 135, 1823–1832 (2008).

    CAS  PubMed  Google Scholar 

  219. Mikawa, T. & Gourdie, R. G. Pericardial mesoderm generates a population of coronary smooth muscle cells migrating into the heart along with ingrowth of the epicardial organ. Dev. Biol. 174, 221–232 (1996).

    CAS  PubMed  Google Scholar 

  220. Hu, Y. et al. Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J. Clin. Invest. 113, 1258–1265 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Kramann, R. et al. Adventitial MSC-like cells are progenitors of vascular smooth muscle cells and drive vascular calcification in chronic kidney disease. Cell Stem Cell 19, 628–642 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Zengin, E. et al. Vascular wall resident progenitor cells: a source for postnatal vasculogenesis. Development 133, 1543–1551 (2006).

    CAS  PubMed  Google Scholar 

  223. Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

    CAS  PubMed  Google Scholar 

  224. Tigges, U., Komatsu, M. & Stallcup, W. B. Adventitial pericyte progenitor/mesenchymal stem cells participate in the restenotic response to arterial injury. J. Vasc. Res. 50, 134–144 (2013).

    CAS  PubMed  Google Scholar 

  225. Parmacek, M. S. Myocardin: dominant driver of the smooth muscle cell contractile phenotype. Arterioscler. Thromb. Vasc. Biol. 28, 1416–1417 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Yoshida, T., Yamashita, M., Horimai, C. & Hayashi, M. Smooth muscle-selective inhibition of nuclear factor-κB attenuates smooth muscle phenotypic switching and neointima formation following vascular injury. J. Am. Heart Assoc. 2, e000230 (2013).

    PubMed  PubMed Central  Google Scholar 

  227. Zhou, A.-X. et al. C/EBP-homologous protein (CHOP) in vascular smooth muscle cells regulates their proliferation in aortic explants and atherosclerotic lesions. Circ. Res. 116, 1736–1743 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Cordes, K. R. et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature 460, 705–710 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Raines, E. W. The extracellular matrix can regulate vascular cell migration, proliferation, and survival: relationships to vascular disease. Int. J. Exp. Pathol. 81, 173–182 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Opitz, F., Schenke-Layland, K., Cohnert, T. U. & Stock, U. A. Phenotypical plasticity of vascular smooth muscle cells-effect of in vitro and in vivo shear stress for tissue engineering of blood vessels. Tissue Eng. 13, 2505–2514 (2007).

    CAS  PubMed  Google Scholar 

  231. Liu, R. et al. Ten-eleven translocation-2 (TET2) is a master regulator of smooth muscle cell plasticity. Circulation 128, 2047–2057 (2013).

    PubMed  PubMed Central  Google Scholar 

  232. Chen, J. et al. Histone demethylase KDM3a, a novel regulator of vascular smooth muscle cells, controls vascular neointimal hyperplasia in diabetic rats. Atherosclerosis 257, 152–163 (2017).

    CAS  PubMed  Google Scholar 

  233. Zhuang, J. et al. The yin-yang dynamics of DNA methylation is the key regulator for smooth muscle cell phenotype switch and vascular remodeling. Arterioscler. Thromb. Vasc. Biol. 37, 84–97 (2017).

    CAS  PubMed  Google Scholar 

  234. Greissel, A. et al. Alternation of histone and DNA methylation in human atherosclerotic carotid plaques. Thromb. Haemost. 114, 390–402 (2015).

    CAS  PubMed  Google Scholar 

  235. Lino Cardenas, C. L. et al. An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. Nat. Commun. 9, 1009 (2018).

    PubMed  PubMed Central  Google Scholar 

  236. Fiedler, J. et al. Non-coding RNAs in vascular disease - from basic science to clinical applications: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology. Cardiovasc. Res. 114, 1281–1286 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Das, S. et al. A novel angiotensin II-induced long noncoding RNA giver regulates oxidative stress, inflammation, and proliferation in vascular smooth muscle cells. Circ. Res. 123, 1298–1312 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Ballantyne, M. D. et al. Smooth muscle enriched long noncoding RNA (SMILR) regulates cell proliferation. Circulation 133, 2050–2065 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Nurnberg, S. T. et al. Coronary artery disease associated transcription factor TCF21 regulates smooth muscle precursor cells that contribute to the fibrous cap. PLOS Genet. 11, e1005155 (2015).

    PubMed  PubMed Central  Google Scholar 

  240. Evrard, S. M. et al. Endothelial to mesenchymal transition is common in atherosclerotic lesions and is associated with plaque instability. Nat. Commun. 7, 11853 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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G.L.B., H.F.J. and M.C.H.C. wrote the manuscript. H.F.J. and M.C.H.C. contributed equally. All the authors researched data for the article, discussed its content, reviewed the manuscript for important intellectual content and edited the manuscript before submission.

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Correspondence to Ziad Mallat.

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The authors declare no competing interests.

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Nature Reviews Cardiology thanks D. M. Greif, P. Libby, M. W. Majesky and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Lineage tracing

Technique that enables the fate of labelled cells to be traced in vivo to allow the identification of progeny cells.

Mesenchymal stem cell

Multipotent stromal cell.

Phenotype switching

Process by which vascular smooth muscle cells (VSMCs) alter their phenotype, often inferred through decreased expression of VSMC-specific genes encoding contractile proteins and/or increased expression of markers typical of synthetic VSMCs or other cell types.

Foam cells

Lipid-laden cells with a foamy appearance.

Osteochondrogenic cells

Cells capable of generating osteocytes and/or chondrocytes.

Clonal expansion

Proliferation of a single or limited number of ancestral cells.

Shelterin complex

Multiprotein complex (including telomeric repeat-binding factor 2 (TRF2)) that binds to the repetitive sequences of telomeric DNA, protecting against DNA damage.

Response to retention hypothesis

Hypothesis that subendothelial retention of lipid, in the form of lipoproteins, is the initial step in atherogenesis.

Vulnerable plaque

Atherosclerotic plaque with a phenotype associated with increased risk of rupture, also known as thin-cap fibroatheromas, defined by a thin fibrous cap (<65 μm) and a large necrotic core.

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Basatemur, G.L., Jørgensen, H.F., Clarke, M.C.H. et al. Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol 16, 727–744 (2019). https://doi.org/10.1038/s41569-019-0227-9

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