Skip to main content
Log in

Lipid accumulation and novel insight into vascular smooth muscle cells in atherosclerosis

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Atherosclerosis is a chronic and progressive process. It is the most important pathological basis of cardiovascular disease and stroke. Vascular smooth muscle cells (VSMCs) are an essential cell type in atherosclerosis. Previous studies have revealed that VSMCs undergo phenotypic transformation in atherosclerosis to participate in the retention of atherogenic lipoproteins as well as the formation of the fibrous cap and the underlying necrotic core in plaques. The emergence of lineage-tracing studies indicates that the function and number of VSMCs in plaques have been greatly underestimated. In addition, recent studies have revealed that VSMCs make up at least 50% of the foam cell population in human and mouse atherosclerotic lesions. Therefore, understanding the formation of lipid-loaded VSMCs and their regulatory mechanisms is critical to elucidate the pathogenesis of atherosclerosis and to explore potential therapeutic targets. Moreover, combination of many complementary technologies such as lineage tracing, single-cell RNA sequencing (scRNA-seq), flow cytometry, and mass cytometry (CyTOF) with immunostaining has been performed to further understand the complex VSMC function. Correct identification of detrimental and beneficial processes may reveal successful therapeutic treatments targeting VSMCs and their derivatives during atherosclerosis. The purpose of this review is to summarize the process of lipid-loaded VSMC formation in atherosclerosis and to describe novel insight into VSMCs gained by using multiple advanced methods.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Herrington W, Lacey B, Sherliker P, Armitage J, Lewington S (2016) Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. Circ Res 118(4):535–546. https://doi.org/10.1161/CIRCRESAHA.115.307611

    Article  PubMed  CAS  Google Scholar 

  2. Basatemur GL, Jorgensen HF, Clarke MCH, Bennett MR, Mallat Z (2019) Vascular smooth muscle cells in atherosclerosis. Nat Rev Cardiol 16(12):727–744. https://doi.org/10.1038/s41569-019-0227-9

    Article  PubMed  Google Scholar 

  3. Bennett MR, Sinha S, Owens GK (2016) Vascular smooth muscle cells in atherosclerosis. Circ Res 118(4):692–702. https://doi.org/10.1161/CIRCRESAHA.115.306361

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Allahverdian S, Chaabane C, Boukais K, Francis GA, Bochaton-Piallat ML (2018) Smooth muscle cell fate and plasticity in atherosclerosis. Cardiovasc Res 114(4):540–550. https://doi.org/10.1093/cvr/cvy022

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Wirka RC, Wagh D, Paik DT, Pjanic M, Nguyen T, Miller CL, Kundu R, Nagao M, Coller J, Koyano TK, Fong R, Woo YJ, Liu B, Montgomery SB, Wu JC, Zhu K, Chang R, Alamprese M, Tallquist MD, Kim JB, Quertermous T (2019) Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis. Nat Med 25(8):1280–1289. https://doi.org/10.1038/s41591-019-0512-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Williams KJ, Tabas I (1995) The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol 15(5):551–561. https://doi.org/10.1161/01.atv.15.5.551

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Tabas I, Williams KJ, Boren J (2007) Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116(16):1832–1844. https://doi.org/10.1161/CIRCULATIONAHA.106.676890

    Article  PubMed  CAS  Google Scholar 

  8. Skalen K, Gustafsson M, Rydberg EK, Hulten LM, Wiklund O, Innerarity TL, Boren J (2002) Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417(6890):750–754. https://doi.org/10.1038/nature00804

    Article  PubMed  CAS  Google Scholar 

  9. Cherepanova OA, Gomez D, Shankman LS, Swiatlowska P, Williams J, Sarmento OF, Alencar GF, Hess DL, Bevard MH, Greene ES, Murgai M, Turner SD, Geng YJ, Bekiranov S, Connelly JJ, Tomilin A, Owens GK (2016) Activation of the pluripotency factor OCT4 in smooth muscle cells is atheroprotective. Nat Med 22(6):657–665. https://doi.org/10.1038/nm.4109

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Chappell J, Harman JL, Narasimhan VM, Yu H, Foote K, Simons BD, Bennett MR, Jorgensen HF (2016) 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(12):1313–1323. https://doi.org/10.1161/CIRCRESAHA.116.309799

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Feil S, Fehrenbacher B, Lukowski R, Essmann F, Schulze-Osthoff K, Schaller M, Feil R (2014) Transdifferentiation of vascular smooth muscle cells to macrophage-like cells during atherogenesis. Circ Res 115(7):662–667. https://doi.org/10.1161/CIRCRESAHA.115.304634

    Article  PubMed  CAS  Google Scholar 

  12. Shankman LS, Gomez D, Cherepanova OA, Salmon M, Alencar GF, Haskins RM, Swiatlowska P, Newman AA, Greene ES, Straub AC, Isakson B, Randolph GJ, Owens GK (2015) KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis. Nat Med 21(6):628–637. https://doi.org/10.1038/nm.3866

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Alencar GF, Owsiany KM, Karnewar S, Sukhavasi K, Mocci G, Nguyen AT, Williams CM, Shamsuzzaman S, Mokry M, Henderson CA, Haskins R, Baylis RA, Finn AV, McNamara CA, Zunder ER, Venkata V, Pasterkamp G, Bjorkegren J, Bekiranov S, Owens GK (2020) Stem cell pluripotency genes Klf4 and Oct4 regulate complex SMC phenotypic changes critical in late-stage atherosclerotic lesion pathogenesis. Circulation 142(21):2045–2059. https://doi.org/10.1161/CIRCULATIONAHA.120.046672

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Allahverdian S, Chehroudi AC, McManus BM, Abraham T, Francis GA (2014) Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation 129(15):1551–1559. https://doi.org/10.1161/CIRCULATIONAHA.113.005015

    Article  PubMed  CAS  Google Scholar 

  15. Wang Y, Dubland JA, Allahverdian S, Asonye E, Sahin B, Jaw JE, Sin DD, Seidman MA, Leeper NJ, Francis GA (2019) Smooth muscle cells contribute the majority of foam cells in ApoE (Apolipoprotein E)-deficient mouse atherosclerosis. Arterioscler Thromb Vasc Biol 39(5):876–887. https://doi.org/10.1161/ATVBAHA.119.312434

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Alique M, Luna C, Carracedo J, Ramirez R (2015) LDL biochemical modifications: a link between atherosclerosis and aging. Food Nutr Res 59:29240. https://doi.org/10.3402/fnr.v59.29240

    Article  PubMed  CAS  Google Scholar 

  17. Bhakdi S, Dorweiler B, Kirchmann R, Torzewski J, Weise E, Tranum-Jensen J, Walev I, Wieland E (1995) On the pathogenesis of atherosclerosis: enzymatic transformation of human low density lipoprotein to an atherogenic moiety. J Exp Med 182(6):1959–1971. https://doi.org/10.1084/jem.182.6.1959

    Article  PubMed  CAS  Google Scholar 

  18. Tertov VV, Sobenin IA, Gabbasov ZA, Popov EG, Orekhov AN (1989) Lipoprotein aggregation as an essential condition of intracellular lipid accumulation caused by modified low density lipoproteins. Biochem Biophys Res Commun 163(1):489–494. https://doi.org/10.1016/0006-291x(89)92163-3

    Article  PubMed  CAS  Google Scholar 

  19. Tertov VV, Orekhov AN, Sobenin IA, Gabbasov ZA, Popov EG, Yaroslavov AA, Smirnov VN (1992) Three types of naturally occurring modified lipoproteins induce intracellular lipid accumulation due to lipoprotein aggregation. Circ Res 71(1):218–228. https://doi.org/10.1161/01.res.71.1.218

    Article  PubMed  CAS  Google Scholar 

  20. Allahverdian S, Pannu PS, Francis GA (2012) Contribution of monocyte-derived macrophages and smooth muscle cells to arterial foam cell formation. Cardiovasc Res 95(2):165–172. https://doi.org/10.1093/cvr/cvs094

    Article  PubMed  CAS  Google Scholar 

  21. Muir EM, Bowyer DE (1983) Dependence of fluid-phase pinocytosis in arterial smooth-muscle cells on temperature, cellular ATP concentration and the cytoskeletal system. Biochem J 216(2):467–473. https://doi.org/10.1042/bj2160467

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Ismail NA, Alavi MZ, Moore S (1994) Lipoprotein-proteoglycan complexes from injured rabbit aortas accelerate lipoprotein uptake by arterial smooth muscle cells. Atherosclerosis 105(1):79–87. https://doi.org/10.1016/0021-9150(94)90010-8

    Article  PubMed  CAS  Google Scholar 

  23. Hiltunen TP, Luoma JS, Nikkari T, Yla-Herttuala S (1998) Expression of LDL receptor, VLDL receptor, LDL receptor-related protein, and scavenger receptor in rabbit atherosclerotic lesions: marked induction of scavenger receptor and VLDL receptor expression during lesion development. Circulation 97(11):1079–1086. https://doi.org/10.1161/01.cir.97.11.1079

    Article  PubMed  CAS  Google Scholar 

  24. Mineo C (2020) Lipoprotein receptor signalling in atherosclerosis. Cardiovasc Res 116(7):1254–1274. https://doi.org/10.1093/cvr/cvz338

    Article  PubMed  CAS  Google Scholar 

  25. Pryma CS, Ortega C, Dubland JA, Francis GA (2019) Pathways of smooth muscle foam cell formation in atherosclerosis. Curr Opin Lipidol 30(2):117–124. https://doi.org/10.1097/MOL.0000000000000574

    Article  PubMed  CAS  Google Scholar 

  26. Moore KJ, Freeman MW (2006) Scavenger receptors in atherosclerosis: beyond lipid uptake. Arterioscler Thromb Vasc Biol 26(8):1702–1711. https://doi.org/10.1161/01.ATV.0000229218.97976.43

    Article  PubMed  CAS  Google Scholar 

  27. Jeon H, Blacklow SC (2005) Structure and physiologic function of the low-density lipoprotein receptor. Annu Rev Biochem 74:535–562. https://doi.org/10.1146/annurev.biochem.74.082803.133354

    Article  PubMed  CAS  Google Scholar 

  28. PrabhuDas MR, Baldwin CL, Bollyky PL, Bowdish DME, Drickamer K, Febbraio M, Herz J, Kobzik L, Krieger M, Loike J, McVicker B, Means TK, Moestrup SK, Post SR, Sawamura T, Silverstein S, Speth RC, Telfer JC, Thiele GM, Wang XY, Wright SD, El Khoury J (2017) A consensus definitive classification of scavenger receptors and their roles in health and disease. J Immunol 198(10):3775–3789. https://doi.org/10.4049/jimmunol.1700373

    Article  PubMed  CAS  Google Scholar 

  29. Zanoni P, Velagapudi S, Yalcinkaya M, Rohrer L, von Eckardstein A (2018) Endocytosis of lipoproteins. Atherosclerosis 275:273–295. https://doi.org/10.1016/j.atherosclerosis.2018.06.881

    Article  PubMed  CAS  Google Scholar 

  30. Strickland DK, Au DT, Cunfer P, Muratoglu SC (2014) Low-density lipoprotein receptor-related protein-1: role in the regulation of vascular integrity. Arterioscler Thromb Vasc Biol 34(3):487–498. https://doi.org/10.1161/ATVBAHA.113.301924

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Luoma J, Hiltunen T, Sarkioja T, Moestrup SK, Gliemann J, Kodama T, Nikkari T, Yla-Herttuala S (1994) Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions. J Clin Invest 93(5):2014–2021. https://doi.org/10.1172/JCI117195

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Llorente-Cortes V, Martinez-Gonzalez J, Badimon L (2000) LDL receptor-related protein mediates uptake of aggregated LDL in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 20(6):1572–1579. https://doi.org/10.1161/01.atv.20.6.1572

    Article  PubMed  CAS  Google Scholar 

  33. Llorente-Cortes V, Otero-Vinas M, Camino-Lopez S, Costales P, Badimon L (2006) Cholesteryl esters of aggregated LDL are internalized by selective uptake in human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 26(1):117–123. https://doi.org/10.1161/01.ATV.0000193618.32611.8b

    Article  PubMed  CAS  Google Scholar 

  34. Suits AG, Chait A, Aviram M, Heinecke JW (1989) Phagocytosis of aggregated lipoprotein by macrophages: low density lipoprotein receptor-dependent foam-cell formation. Proc Natl Acad Sci U S A 86(8):2713–2717. https://doi.org/10.1073/pnas.86.8.2713

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Llorente-Cortes V, Otero-Vinas M, Sanchez S, Rodriguez C, Badimon L (2002) Low-density lipoprotein upregulates low-density lipoprotein receptor-related protein expression in vascular smooth muscle cells: possible involvement of sterol regulatory element binding protein-2-dependent mechanism. Circulation 106(24):3104–3110. https://doi.org/10.1161/01.cir.0000041434.28573.0b

    Article  PubMed  CAS  Google Scholar 

  36. Costales P, Aledo R, Vernia S, Das A, Shah VH, Casado M, Badimon L, Llorente-Cortes V (2010) Selective role of sterol regulatory element binding protein isoforms in aggregated LDL-induced vascular low density lipoprotein receptor-related protein-1 expression. Atherosclerosis 213(2):458–468. https://doi.org/10.1016/j.atherosclerosis.2010.09.034

    Article  PubMed  CAS  Google Scholar 

  37. Llorente-Cortes V, Costales P, Bernues J, Camino-Lopez S, Badimon L (2006) Sterol regulatory element-binding protein-2 negatively regulates low density lipoprotein receptor-related protein transcription. J Mol Biol 359(4):950–960. https://doi.org/10.1016/j.jmb.2006.04.008

    Article  PubMed  CAS  Google Scholar 

  38. Costales P, Fuentes-Prior P, Castellano J, Revuelta-Lopez E, Corral-Rodriguez MA, Nasarre L, Badimon L, Llorente-Cortes V (2015) K Domain CR9 of low density lipoprotein (LDL) receptor-related protein 1 (LRP1) is critical for aggregated LDL-induced foam cell formation from human vascular smooth muscle cells. J Biol Chem 290(24):14852–14865. https://doi.org/10.1074/jbc.M115.638361

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Dissmore T, Seye CI, Medeiros DM, Weisman GA, Bradford B, Mamedova L (2016) The P2Y2 receptor mediates uptake of matrix-retained and aggregated low density lipoprotein in primary vascular smooth muscle cells. Atherosclerosis 252:128–135. https://doi.org/10.1016/j.atherosclerosis.2016.07.927

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Gordts PL, Reekmans S, Lauwers A, Van Dongen A, Verbeek L, Roebroek AJ (2009) Inactivation of the LRP1 intracellular NPxYxxL motif in LDLR-deficient mice enhances postprandial dyslipidemia and atherosclerosis. Arterioscler Thromb Vasc Biol 29(9):1258–1264. https://doi.org/10.1161/ATVBAHA.109.192211

    Article  PubMed  CAS  Google Scholar 

  41. Boucher P, Gotthardt M, Li WP, Anderson RG, Herz J (2003) LRP: role in vascular wall integrity and protection from atherosclerosis. Science 300(5617):329–332. https://doi.org/10.1126/science.1082095

    Article  PubMed  CAS  Google Scholar 

  42. Basford JE, Moore ZW, Zhou L, Herz J, Hui DY (2009) Smooth muscle LDL receptor-related protein-1 inactivation reduces vascular reactivity and promotes injury-induced neointima formation. Arterioscler Thromb Vasc Biol 29(11):1772–1778. https://doi.org/10.1161/ATVBAHA.109.194357

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Goldstein JL, Brown MS (1977) The low-density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem 46:897–930. https://doi.org/10.1146/annurev.bi.46.070177.004341

    Article  PubMed  CAS  Google Scholar 

  44. Goldstein JL, Brown MS (2009) The LDL receptor. Arterioscler Thromb Vasc Biol 29(4):431–438. https://doi.org/10.1161/ATVBAHA.108.179564

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Multhaupt HA, Gafvels ME, Kariko K, Jin H, Arenas-Elliot C, Goldman BI, Strauss JF, 3rd, Angelin B, Warhol MJ, McCrae KR (1996) Expression of very low density lipoprotein receptor in the vascular wall. Analysis of human tissues by in situ hybridization and immunohistochemistry. Am J Pathol 148 (6):1985–1997

  46. Tacken PJ, Teusink B, Jong MC, Harats D, Havekes LM, van Dijk KW, Hofker MH (2000) LDL receptor deficiency unmasks altered VLDL triglyceride metabolism in VLDL receptor transgenic and knockout mice. J Lipid Res 41(12):2055–2062

    Article  CAS  PubMed  Google Scholar 

  47. Argmann CA, Sawyez CG, Li S, Nong Z, Hegele RA, Pickering JG, Huff MW (2004) Human smooth muscle cell subpopulations differentially accumulate cholesteryl ester when exposed to native and oxidized lipoproteins. Arterioscler Thromb Vasc Biol 24(7):1290–1296. https://doi.org/10.1161/01.ATV.0000131260.80316.37

    Article  PubMed  CAS  Google Scholar 

  48. Frontini MJ, O’Neil C, Sawyez C, Chan BM, Huff MW, Pickering JG (2009) Lipid incorporation inhibits Src-dependent assembly of fibronectin and type I collagen by vascular smooth muscle cells. Circ Res 104(7):832–841. https://doi.org/10.1161/CIRCRESAHA.108.187302

    Article  PubMed  CAS  Google Scholar 

  49. Okada SS, Grobmyer SR, Barnathan ES (1996) Contrasting effects of plasminogen activators, urokinase receptor, and LDL receptor-related protein on smooth muscle cell migration and invasion. Arterioscler Thromb Vasc Biol 16(10):1269–1276. https://doi.org/10.1161/01.atv.16.10.1269

    Article  PubMed  CAS  Google Scholar 

  50. Wijnberg MJ, Quax PH, Nieuwenbroek NM, Verheijen JH (1997) The migration of human smooth muscle cells in vitro is mediated by plasminogen activation and can be inhibited by alpha2-macroglobulin receptor associated protein. Thromb Haemost 78(2):880–886

    Article  CAS  PubMed  Google Scholar 

  51. Brown MS, Goldstein JL (1986) A receptor-mediated pathway for cholesterol homeostasis. Science 232(4746):34–47. https://doi.org/10.1126/science.3513311

    Article  PubMed  CAS  Google Scholar 

  52. Goldstein JL, Brown MS (2015) A century of cholesterol and coronaries: from plaques to genes to statins. Cell 161(1):161–172. https://doi.org/10.1016/j.cell.2015.01.036

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Ruan XZ, Moorhead JF, Tao JL, Ma KL, Wheeler DC, Powis SH, Varghese Z (2006) Mechanisms of dysregulation of low-density lipoprotein receptor expression in vascular smooth muscle cells by inflammatory cytokines. Arterioscler Thromb Vasc Biol 26(5):1150–1155. https://doi.org/10.1161/01.ATV.0000217957.93135.c2

    Article  PubMed  CAS  Google Scholar 

  54. Ma KL, Ruan XZ, Powis SH, Moorhead JF, Varghese Z (2007) Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 292(6):H2721-2728. https://doi.org/10.1152/ajpheart.01174.2006

    Article  PubMed  CAS  Google Scholar 

  55. Zani IA, Stephen SL, Mughal NA, Russell D, Homer-Vanniasinkam S, Wheatcroft SB, Ponnambalam S (2015) Scavenger receptor structure and function in health and disease. Cells 4(2):178–201. https://doi.org/10.3390/cells4020178

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Kodama T, Freeman M, Rohrer L, Zabrecky J, Matsudaira P, Krieger M (1990) Type I macrophage scavenger receptor contains alpha-helical and collagen-like coiled coils. Nature 343(6258):531–535. https://doi.org/10.1038/343531a0

    Article  PubMed  CAS  Google Scholar 

  57. Naito M, Suzuki H, Mori T, Matsumoto A, Kodama T, Takahashi K (1992) Coexpression of type I and type II human macrophage scavenger receptors in macrophages of various organs and foam cells in atherosclerotic lesions. Am J Pathol 141(3):591–599

    PubMed  PubMed Central  CAS  Google Scholar 

  58. Li H, Freeman MW, Libby P (1995) Regulation of smooth muscle cell scavenger receptor expression in vivo by atherogenic diets and in vitro by cytokines. J Clin Invest 95(1):122–133. https://doi.org/10.1172/JCI117628

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Daugherty A, Cornicelli JA, Welch K, Sendobry SM, Rateri DL (1997) Scavenger receptors are present on rabbit aortic endothelial cells in vivo. Arterioscler Thromb Vasc Biol 17(11):2369–2375. https://doi.org/10.1161/01.atv.17.11.2369

    Article  PubMed  CAS  Google Scholar 

  60. Suzuki H, Kurihara Y, Takeya M, Kamada N, Kataoka M, Jishage K, Ueda O, Sakaguchi H, Higashi T, Suzuki T, Takashima Y, Kawabe Y, Cynshi O, Wada Y, Honda M, Kurihara H, Aburatani H, Doi T, Matsumoto A, Azuma S, Noda T, Toyoda Y, Itakura H, Yazaki Y, Kodama T et al (1997) A role for macrophage scavenger receptors in atherosclerosis and susceptibility to infection. Nature 386 (6622):292–296. https://doi.org/10.1038/386292a0

  61. Mietus-Snyder M, Gowri MS, Pitas RE (2000) Class A scavenger receptor up-regulation in smooth muscle cells by oxidized low density lipoprotein. Enhancement by calcium flux and concurrent cyclooxygenase-2 up-regulation. J Biol Chem 275 (23):17661–17670. https://doi.org/10.1074/jbc.275.23.17661

  62. Yan P, Xia C, Duan C, Li S, Mei Z (2011) Biological characteristics of foam cell formation in smooth muscle cells derived from bone marrow stem cells. Int J Biol Sci 7(7):937–946. https://doi.org/10.7150/ijbs.7.937

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Matsumoto K, Hirano K, Nozaki S, Takamoto A, Nishida M, Nakagawa-Toyama Y, Janabi MY, Ohya T, Yamashita S, Matsuzawa Y (2000) Expression of macrophage (Mphi) scavenger receptor, CD36, in cultured human aortic smooth muscle cells in association with expression of peroxisome proliferator activated receptor-gamma, which regulates gain of Mphi-like phenotype in vitro, and its implication in atherogenesis. Arterioscler Thromb Vasc Biol 20(4):1027–1032. https://doi.org/10.1161/01.atv.20.4.1027

    Article  PubMed  CAS  Google Scholar 

  64. Swerlick RA, Lee KH, Wick TM, Lawley TJ (1992) Human dermal microvascular endothelial but not human umbilical vein endothelial cells express CD36 in vivo and in vitro. J Immunol 148(1):78–83

    PubMed  CAS  Google Scholar 

  65. Tandon NN, Lipsky RH, Burgess WH, Jamieson GA (1989) Isolation and characterization of platelet glycoprotein IV (CD36). J Biol Chem 264(13):7570–7575

    Article  CAS  PubMed  Google Scholar 

  66. Yue H, Febbraio M, Klenotic PA, Kennedy DJ, Wu Y, Chen S, Gohara AF, Li O, Belcher A, Kuang B, McIntyre TM, Silverstein RL, Li W (2019) CD36 enhances vascular smooth muscle cell proliferation and development of neointimal hyperplasia. Arterioscler Thromb Vasc Biol 39(2):263–275. https://doi.org/10.1161/ATVBAHA.118.312186

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Endemann G, Stanton LW, Madden KS, Bryant CM, White RT, Protter AA (1993) CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem 268(16):11811–11816

    Article  CAS  PubMed  Google Scholar 

  68. Ma S, Yang D, Li D, Tang B, Yang Y (2011) Oleic acid induces smooth muscle foam cell formation and enhances atherosclerotic lesion development via CD36. Lipids Health Dis 10:53. https://doi.org/10.1186/1476-511X-10-53

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Chen Q, Reis SE, Kammerer C, Craig WY, LaPierre SE, Zimmer EL, McNamara DM, Pauly DF, Sharaf B, Holubkov R, Bairey Merz CN, Sopko G, Bontempo F, Kamboh MI (2003) Genetic variation in lectin-like oxidized low-density lipoprotein receptor 1 (LOX1) gene and the risk of coronary artery disease. Circulation 107(25):3146–3151. https://doi.org/10.1161/01.CIR.0000074207.85796.36

    Article  PubMed  CAS  Google Scholar 

  70. Kataoka H, Kume N, Miyamoto S, Minami M, Moriwaki H, Murase T, Sawamura T, Masaki T, Hashimoto N, Kita T (1999) Expression of lectinlike oxidized low-density lipoprotein receptor-1 in human atherosclerotic lesions. Circulation 99(24):3110–3117. https://doi.org/10.1161/01.cir.99.24.3110

    Article  PubMed  CAS  Google Scholar 

  71. Chen M, Kakutani M, Naruko T, Ueda M, Narumiya S, Masaki T, Sawamura T (2001) Activation-dependent surface expression of LOX-1 in human platelets. Biochem Biophys Res Commun 282(1):153–158. https://doi.org/10.1006/bbrc.2001.4516

    Article  PubMed  CAS  Google Scholar 

  72. Sun Y, Chen X (2011) Ox-LDL-induced LOX-1 expression in vascular smooth muscle cells: role of reactive oxygen species. Fundam Clin Pharmacol 25(5):572–579. https://doi.org/10.1111/j.1472-8206.2010.00885.x

    Article  PubMed  CAS  Google Scholar 

  73. Chellan B, Reardon CA, Getz GS, Hofmann Bowman MA (2016) Enzymatically modified low-density lipoprotein promotes foam cell formation in smooth muscle cells via macropinocytosis and enhances receptor-mediated uptake of oxidized low-density lipoprotein. Arterioscler Thromb Vasc Biol 36(6):1101–1113. https://doi.org/10.1161/ATVBAHA.116.307306

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Eto H, Miyata M, Kume N, Minami M, Itabe H, Orihara K, Hamasaki S, Biro S, Otsuji Y, Kita T, Tei C (2006) Expression of lectin-like oxidized LDL receptor-1 in smooth muscle cells after vascular injury. Biochem Biophys Res Commun 341(2):591–598. https://doi.org/10.1016/j.bbrc.2005.12.211

    Article  PubMed  CAS  Google Scholar 

  75. Hinagata J, Kakutani M, Fujii T, Naruko T, Inoue N, Fujita Y, Mehta JL, Ueda M, Sawamura T (2006) Oxidized LDL receptor LOX-1 is involved in neointimal hyperplasia after balloon arterial injury in a rat model. Cardiovasc Res 69(1):263–271. https://doi.org/10.1016/j.cardiores.2005.08.013

    Article  PubMed  CAS  Google Scholar 

  76. Kataoka H, Kume N, Miyamoto S, Minami M, Morimoto M, Hayashida K, Hashimoto N, Kita T (2001) Oxidized LDL modulates Bax/Bcl-2 through the lectinlike Ox-LDL receptor-1 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 21(6):955–960. https://doi.org/10.1161/01.atv.21.6.955

    Article  PubMed  CAS  Google Scholar 

  77. Chen J, Mehta JL, Haider N, Zhang X, Narula J, Li D (2004) Role of caspases in Ox-LDL-induced apoptotic cascade in human coronary artery endothelial cells. Circ Res 94(3):370–376. https://doi.org/10.1161/01.RES.0000113782.07824.BE

    Article  PubMed  CAS  Google Scholar 

  78. Wagsater D, Olofsson PS, Norgren L, Stenberg B, Sirsjo A (2004) The chemokine and scavenger receptor CXCL16/SR-PSOX is expressed in human vascular smooth muscle cells and is induced by interferon gamma. Biochem Biophys Res Commun 325(4):1187–1193. https://doi.org/10.1016/j.bbrc.2004.10.160

    Article  PubMed  CAS  Google Scholar 

  79. Minami M, Kume N, Shimaoka T, Kataoka H, Hayashida K, Akiyama Y, Nagata I, Ando K, Nobuyoshi M, Hanyuu M, Komeda M, Yonehara S, Kita T (2001) Expression of SR-PSOX, a novel cell-surface scavenger receptor for phosphatidylserine and oxidized LDL in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 21(11):1796–1800. https://doi.org/10.1161/hq1001.096652

    Article  PubMed  CAS  Google Scholar 

  80. Hofnagel O, Luechtenborg B, Plenz G, Robenek H (2002) Expression of the novel scavenger receptor SR-PSOX in cultured aortic smooth muscle cells and umbilical endothelial cells. Arterioscler Thromb Vasc Biol 22(4):710–711. https://doi.org/10.1161/01.atv.0000012402.85056.45

    Article  PubMed  CAS  Google Scholar 

  81. Rong JX, Shapiro M, Trogan E, Fisher EA (2003) Transdifferentiation of mouse aortic smooth muscle cells to a macrophage-like state after cholesterol loading. Proc Natl Acad Sci U S A 100(23):13531–13536. https://doi.org/10.1073/pnas.1735526100

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Vengrenyuk Y, Nishi H, Long X, Ouimet M, Savji N, Martinez FO, Cassella CP, Moore KJ, Ramsey SA, Miano JM, Fisher EA (2015) 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(3):535–546. https://doi.org/10.1161/ATVBAHA.114.304029

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Petrichenko IE, Daret D, Kolpakova GV, Shakhov YA, Larrue J (1997) Glucocorticoids stimulate cholesteryl ester formation in human smooth muscle cells. Arterioscler Thromb Vasc Biol 17(6):1143–1151. https://doi.org/10.1161/01.atv.17.6.1143

    Article  PubMed  CAS  Google Scholar 

  84. Ouimet M, Franklin V, Mak E, Liao X, Tabas I, Marcel YL (2011) Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab 13(6):655–667. https://doi.org/10.1016/j.cmet.2011.03.023

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Pi S, Mao L, Chen J, Shi H, Liu Y, Guo X, Li Y, Zhou L, He H, Yu C, Liu J, Dang Y, Xia Y, He Q, Jin H, Li Y, Hu Y, Miao Y, Yue Z, Hu B (2020) The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis. Autophagy 1–21. https://doi.org/10.1080/15548627.2020.1741202

  86. Yin YW, Liao SQ, Zhang MJ, Liu Y, Li BH, Zhou Y, Chen L, Gao CY, Li JC, Zhang LL (2014) TLR4-mediated inflammation promotes foam cell formation of vascular smooth muscle cell by upregulating ACAT1 expression. Cell Death Dis 5:e1574. https://doi.org/10.1038/cddis.2014.535

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Dubland JA, Francis GA (2015) Lysosomal acid lipase: at the crossroads of normal and atherogenic cholesterol metabolism. Front Cell Dev Biol 3:3. https://doi.org/10.3389/fcell.2015.00003

    Article  PubMed  PubMed Central  Google Scholar 

  88. Mulas MF, Maxia A, Dessi S, Mandas A (2014) Cholesterol esterification as a mediator of proliferation of vascular smooth muscle cells and peripheral blood mononuclear cells during atherogenesis. J Vasc Res 51(1):14–26. https://doi.org/10.1159/000355218

    Article  PubMed  CAS  Google Scholar 

  89. Rong JX, Kusunoki J, Oelkers P, Sturley SL, Fisher EA (2005) Acyl-coenzymeA (CoA):cholesterol acyltransferase inhibition in rat and human aortic smooth muscle cells is nontoxic and retards foam cell formation. Arterioscler Thromb Vasc Biol 25(1):122–127. https://doi.org/10.1161/01.ATV.0000148202.49842.3b

    Article  PubMed  CAS  Google Scholar 

  90. Yancey PG, Bortnick AE, Kellner-Weibel G, de la Llera-Moya M, Phillips MC, Rothblat GH (2003) Importance of different pathways of cellular cholesterol efflux. Arterioscler Thromb Vasc Biol 23(5):712–719. https://doi.org/10.1161/01.ATV.0000057572.97137.DD

    Article  PubMed  CAS  Google Scholar 

  91. Zhao D, Li J, Xue C, Feng K, Liu L, Zeng P, Wang X, Chen Y, Li L, Zhang Z, Duan Y, Han J, Yang X (2020) TL1A inhibits atherosclerosis in apoE-deficient mice by regulating the phenotype of vascular smooth muscle cells. J Biol Chem 295(48):16314–16327. https://doi.org/10.1074/jbc.RA120.015486

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  92. Ishikawa Y, Kimura-Matsumoto M, Murakami M, Murakami M, Yamamoto K, Akasaka Y, Uzuki M, Yuri Y, Inomata N, Yokoo T, Ishii T (2009) Distribution of smooth muscle cells and macrophages expressing scavenger receptor BI/II in atherosclerosis. J Atheroscler Thromb 16(6):829–839. https://doi.org/10.5551/jat.1941

    Article  PubMed  CAS  Google Scholar 

  93. Dean M, Hamon Y, Chimini G (2001) The human ATP-binding cassette (ABC) transporter superfamily. J Lipid Res 42(7):1007–1017

    Article  CAS  PubMed  Google Scholar 

  94. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB, Duverger N, Denefle P, Assmann G (1999) Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22(4):352–355. https://doi.org/10.1038/11921

    Article  PubMed  CAS  Google Scholar 

  95. Remaley AT, Stonik JA, Demosky SJ, Neufeld EB, Bocharov AV, Vishnyakova TG, Eggerman TL, Patterson AP, Duverger NJ, Santamarina-Fojo S, Brewer HB Jr (2001) Apolipoprotein specificity for lipid efflux by the human ABCAI transporter. Biochem Biophys Res Commun 280(3):818–823. https://doi.org/10.1006/bbrc.2000.4219

    Article  PubMed  CAS  Google Scholar 

  96. Oram JF, Heinecke JW (2005) ATP-binding cassette transporter A1: a cell cholesterol exporter that protects against cardiovascular disease. Physiol Rev 85(4):1343–1372. https://doi.org/10.1152/physrev.00005.2005

    Article  PubMed  CAS  Google Scholar 

  97. Gelissen IC, Harris M, Rye KA, Quinn C, Brown AJ, Kockx M, Cartland S, Packianathan M, Kritharides L, Jessup W (2006) ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I. Arterioscler Thromb Vasc Biol 26(3):534–540. https://doi.org/10.1161/01.ATV.0000200082.58536.e1

    Article  PubMed  CAS  Google Scholar 

  98. Vaughan AM, Oram JF (2006) ABCA1 and ABCG1 or ABCG4 act sequentially to remove cellular cholesterol and generate cholesterol-rich HDL. J Lipid Res 47(11):2433–2443. https://doi.org/10.1194/jlr.M600218-JLR200

    Article  PubMed  CAS  Google Scholar 

  99. Cao X, Zhang L, Chen C, Wang Q, Guo L, Ma Q, Deng P, Zhu G, Li B, Pi Y, Long C, Zhang L, Yu Z, Zhou Z, Li J (2017) The critical role of ABCG1 and PPARgamma/LXRalpha signaling in TLR4 mediates inflammatory responses and lipid accumulation in vascular smooth muscle cells. Cell Tissue Res 368(1):145–157. https://doi.org/10.1007/s00441-016-2518-3

    Article  PubMed  CAS  Google Scholar 

  100. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M (1996) Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271(5248):518–520. https://doi.org/10.1126/science.271.5248.518

    Article  PubMed  CAS  Google Scholar 

  101. Ashraf MZ, Gupta N (2011) Scavenger receptors: implications in atherothrombotic disorders. Int J Biochem Cell Biol 43(5):697–700. https://doi.org/10.1016/j.biocel.2011.01.019

    Article  PubMed  CAS  Google Scholar 

  102. Yeh YC, Hwang GY, Liu IP, Yang VC (2002) Identification and expression of scavenger receptor SR-BI in endothelial cells and smooth muscle cells of rat aorta in vitro and in vivo. Atherosclerosis 161(1):95–103. https://doi.org/10.1016/s0021-9150(01)00642-6

    Article  PubMed  CAS  Google Scholar 

  103. Tedgui A, Mallat Z (2006) Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 86(2):515–581. https://doi.org/10.1152/physrev.00024.2005

    Article  PubMed  CAS  Google Scholar 

  104. Chang MY, Potter-Perigo S, Tsoi C, Chait A, Wight TN (2000) 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(7):4766–4773. https://doi.org/10.1074/jbc.275.7.4766

    Article  PubMed  CAS  Google Scholar 

  105. Heltianu C, Robciuc A, Botez G, Musina C, Stancu C, Sima AV, Simionescu M (2011) Modified low density lipoproteins decrease the activity and expression of lysosomal acid lipase in human endothelial and smooth muscle cells. Cell Biochem Biophys 61(1):209–216. https://doi.org/10.1007/s12013-011-9190-8

    Article  PubMed  CAS  Google Scholar 

  106. Gabunia K, Herman AB, Ray M, Kelemen SE, England RN, DeLa CR, Foster WJ, Elliott KJ, Eguchi S, Autieri MV (2017) Induction of MiR133a expression by IL-19 targets LDLRAP1 and reduces oxLDL uptake in VSMC. J Mol Cell Cardiol 105:38–48. https://doi.org/10.1016/j.yjmcc.2017.02.005

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Chan CY, Chan YC, Cheuk BL, Cheng SW (2017) Clearance of matrix metalloproteinase-9 is dependent on low-density lipoprotein receptor-related protein-1 expression downregulated by microRNA-205 in human abdominal aortic aneurysm. J Vasc Surg 65(2):509–520. https://doi.org/10.1016/j.jvs.2015.10.065

    Article  PubMed  Google Scholar 

  108. Cai C, Zhu H, Ning X, Li L, Yang B, Chen S, Wang L, Lu X, Gu D (2019) LncRNA ENST00000602558.1 regulates ABCG1 expression and cholesterol efflux from vascular smooth muscle cells through a p65-dependent pathway. Atherosclerosis 285:31–39. https://doi.org/10.1016/j.atherosclerosis.2019.04.204

    Article  PubMed  CAS  Google Scholar 

  109. Xu BM, Xiao L, Kang CM, Ding L, Guo FX, Li P, Lu ZF, Wu Q, Xu YJ, Bai HL, Tang JY, Zheng L, Hu YW, Wang Q (2019) LncRNA AC096664.3/PPAR-gamma/ABCG1-dependent signal transduction pathway contributes to the regulation of cholesterol homeostasis. J Cell Biochem 120(8):13775–13782. https://doi.org/10.1002/jcb.28650

  110. Otero-Vinas M, Llorente-Cortes V, Pena E, Padro T, Badimon L (2007) Aggregated low density lipoproteins decrease metalloproteinase-9 expression and activity in human coronary smooth muscle cells. Atherosclerosis 194(2):326–333. https://doi.org/10.1016/j.atherosclerosis.2006.10.021

    Article  PubMed  CAS  Google Scholar 

  111. Klouche M, Rose-John S, Schmiedt W, Bhakdi S (2000) Enzymatically degraded, nonoxidized LDL induces human vascular smooth muscle cell activation, foam cell transformation, and proliferation. Circulation 101(15):1799–1805. https://doi.org/10.1161/01.cir.101.15.1799

    Article  PubMed  CAS  Google Scholar 

  112. Barlic J, Zhang Y, Murphy PM (2007) Atherogenic lipids induce adhesion of human coronary artery smooth muscle cells to macrophages by up-regulating chemokine CX3CL1 on smooth muscle cells in a TNFalpha-NFkappaB-dependent manner. J Biol Chem 282(26):19167–19176. https://doi.org/10.1074/jbc.M701642200

    Article  PubMed  CAS  Google Scholar 

  113. Wolf D, Ley K (2019) Immunity and Inflammation in Atherosclerosis. Circ Res 124(2):315–327. https://doi.org/10.1161/CIRCRESAHA.118.313591

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Chen L, Ishigami T, Doi H, Arakawa K, Tamura K (2020) Gut microbiota and atherosclerosis: role of B cell for atherosclerosis focusing on the gut-immune-B2 cell axis. J Mol Med (Berl) 98(9):1235–1244. https://doi.org/10.1007/s00109-020-01936-5

  115. Kim S, Cho W, Kim I, Lee SH, Oh GT, Park YM (2020) Oxidized LDL induces vimentin secretion by macrophages and contributes to atherosclerotic inflammation. J Mol Med (Berl) 98(7):973–983. https://doi.org/10.1007/s00109-020-01923-w

    Article  CAS  Google Scholar 

  116. Yahagi K, Kolodgie FD, Otsuka F, Finn AV, Davis HR, Joner M, Virmani R (2016) Pathophysiology of native coronary, vein graft, and in-stent atherosclerosis. Nat Rev Cardiol 13(2):79–98. https://doi.org/10.1038/nrcardio.2015.164

    Article  PubMed  CAS  Google Scholar 

  117. Campbell JH, Rennick RE, Kalevitch SG, Campbell GR (1992) Heparan sulfate-degrading enzymes induce modulation of smooth muscle phenotype. Exp Cell Res 200(1):156–167. https://doi.org/10.1016/s0014-4827(05)80084-9

    Article  PubMed  CAS  Google Scholar 

  118. Vijayagopal P, Glancy DL (1996) Macrophages stimulate cholesteryl ester accumulation in cocultured smooth muscle cells incubated with lipoprotein-proteoglycan complex. Arterioscler Thromb Vasc Biol 16(9):1112–1121. https://doi.org/10.1161/01.atv.16.9.1112

    Article  PubMed  CAS  Google Scholar 

  119. Weinert S, Poitz DM, Auffermann-Gretzinger S, Eger L, Herold J, Medunjanin S, Schmeisser A, Strasser RH, Braun-Dullaeus RC (2013) The lysosomal transfer of LDL/cholesterol from macrophages into vascular smooth muscle cells induces their phenotypic alteration. Cardiovasc Res 97(3):544–552. https://doi.org/10.1093/cvr/cvs367

    Article  PubMed  CAS  Google Scholar 

  120. Wolfbauer G, Glick JM, Minor LK, Rothblat GH (1986) Development of the smooth muscle foam cell: uptake of macrophage lipid inclusions. Proc Natl Acad Sci U S A 83(20):7760–7764. https://doi.org/10.1073/pnas.83.20.7760

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Davies PF, Truskey GA, Warren HB, O’Connor SE, Eisenhaure BH (1985) Metabolic cooperation between vascular endothelial cells and smooth muscle cells in co-culture: changes in low density lipoprotein metabolism. J Cell Biol 101(3):871–879. https://doi.org/10.1083/jcb.101.3.871

    Article  PubMed  CAS  Google Scholar 

  122. Hajjar DP, Falcone DJ, Amberson JB, Hefton JM (1985) Interaction of arterial cells. I. Endothelial cells alter cholesterol metabolism in co-cultured smooth muscle cells. J Lipid Res 26(10):1212–1223

  123. Aqel NM, Ball RY, Waldmann H, Mitchinson MJ (1985) Identification of macrophages and smooth muscle cells in human atherosclerosis using monoclonal antibodies. J Pathol 146(3):197–204. https://doi.org/10.1002/path.1711460306

    Article  PubMed  CAS  Google Scholar 

  124. Owsiany KM, Alencar GF, Owens GK (2019) Revealing the Origins of Foam Cells in Atherosclerotic Lesions. Arterioscler Thromb Vasc Biol 39(5):836–838. https://doi.org/10.1161/ATVBAHA.119.312557

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Gomez D, Shankman LS, Nguyen AT, Owens GK (2013) Detection of histone modifications at specific gene loci in single cells in histological sections. Nat Methods 10(2):171–177. https://doi.org/10.1038/nmeth.2332

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Jacobsen K, Lund MB, Shim J, Gunnersen S, Fuchtbauer EM, Kjolby M, Carramolino L, Bentzon JF (2017) Diverse cellular architecture of atherosclerotic plaque derives from clonal expansion of a few medial SMCs. JCI Insight 2(19). https://doi.org/10.1172/jci.insight.95890

  127. Misra A, Feng Z, Chandran RR, Kabir I, Rotllan N, Aryal B, Sheikh AQ, Ding L, Qin L, Fernandez-Hernando C, Tellides G, Greif DM (2018) Integrin beta3 regulates clonality and fate of smooth muscle-derived atherosclerotic plaque cells. Nat Commun 9(1):2073. https://doi.org/10.1038/s41467-018-04447-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  128. Back M, Yurdagul A Jr, Tabas I, Oorni K, Kovanen PT (2019) Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol 16(7):389–406. https://doi.org/10.1038/s41569-019-0169-2

    Article  PubMed  PubMed Central  Google Scholar 

  129. Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, Asano M, Moriwaki H, Seishima M (2003) Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 23(4):656–660. https://doi.org/10.1161/01.ATV.0000064374.15232.C3

    Article  PubMed  CAS  Google Scholar 

  130. Chi H, Messas E, Levine RA, Graves DT, Amar S (2004) Interleukin-1 receptor signaling mediates atherosclerosis associated with bacterial exposure and/or a high-fat diet in a murine apolipoprotein E heterozygote model: pharmacotherapeutic implications. Circulation 110(12):1678–1685. https://doi.org/10.1161/01.CIR.0000142085.39015.31

    Article  PubMed  CAS  Google Scholar 

  131. Bhaskar V, Yin J, Mirza AM, Phan D, Vanegas S, Issafras H, Michelson K, Hunter JJ, Kantak SS (2011) Monoclonal antibodies targeting IL-1 beta reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in Apolipoprotein E-deficient mice. Atherosclerosis 216(2):313–320. https://doi.org/10.1016/j.atherosclerosis.2011.02.026

    Article  CAS  PubMed  Google Scholar 

  132. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, Group CT (2017) Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 377(12):1119–1131. https://doi.org/10.1056/NEJMoa1707914

    Article  Google Scholar 

  133. Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ, Group CT (2018) Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 391(10118):319–328. https://doi.org/10.1016/S0140-6736(17)32814-3

    Article  Google Scholar 

  134. Gomez D, Baylis RA, Durgin BG, Newman AAC, Alencar GF, Mahan S, St Hilaire C, Muller W, Waisman A, Francis SE, Pinteaux E, Randolph GJ, Gram H, Owens GK (2018) Interleukin-1beta has atheroprotective effects in advanced atherosclerotic lesions of mice. Nat Med 24(9):1418–1429. https://doi.org/10.1038/s41591-018-0124-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Wang Y, Nanda V, Direnzo D, Ye J, Xiao S, Kojima Y, Howe KL, Jarr KU, Flores AM, Tsantilas P, Tsao N, Rao A, Newman AAC, Eberhard AV, Priest JR, Ruusalepp A, Pasterkamp G, Maegdefessel L, Miller CL, Lind L, Koplev S, Bjorkegren JLM, Owens GK, Ingelsson E, Weissman IL, Leeper NJ (2020) Clonally expanding smooth muscle cells promote atherosclerosis by escaping efferocytosis and activating the complement cascade. Proc Natl Acad Sci U S A 117(27):15818–15826. https://doi.org/10.1073/pnas.2006348117

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Dobnikar L, Taylor AL, Chappell J, Oldach P, Harman JL, Oerton E, Dzierzak E, Bennett MR, Spivakov M, Jorgensen HF (2018) Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels. Nat Commun 9(1):4567. https://doi.org/10.1038/s41467-018-06891-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Winkels H, Ehinger E, Vassallo M, Buscher K, Dinh HQ, Kobiyama K, Hamers AAJ, Cochain C, Vafadarnejad E, Saliba AE, Zernecke A, Pramod AB, Ghosh AK, Anto Michel N, Hoppe N, Hilgendorf I, Zirlik A, Hedrick CC, Ley K, Wolf D (2018) Atlas of the Immune Cell Repertoire in Mouse Atherosclerosis Defined by Single-Cell RNA-Sequencing and Mass Cytometry. Circ Res 122(12):1675–1688. https://doi.org/10.1161/CIRCRESAHA.117.312513

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Fernandez DM, Rahman AH, Fernandez NF, Chudnovskiy A, Amir ED, Amadori L, Khan NS, Wong CK, Shamailova R, Hill CA, Wang Z, Remark R, Li JR, Pina C, Faries C, Awad AJ, Moss N, Bjorkegren JLM, Kim-Schulze S, Gnjatic S, Ma’ayan A, Mocco J, Faries P, Merad M, Giannarelli C (2019) Single-cell immune landscape of human atherosclerotic plaques. Nat Med 25(10):1576–1588. https://doi.org/10.1038/s41591-019-0590-4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Cochain C, Vafadarnejad E, Arampatzi P, Pelisek J, Winkels H, Ley K, Wolf D, Saliba AE, Zernecke A (2018) Single-cell RNA-Seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ Res 122(12):1661–1674. https://doi.org/10.1161/CIRCRESAHA.117.312509

    Article  PubMed  CAS  Google Scholar 

  140. Kim K, Shim D, Lee JS, Zaitsev K, Williams JW, Kim KW, Jang MY, Seok Jang H, Yun TJ, Lee SH, Yoon WK, Prat A, Seidah NG, Choi J, Lee SP, Yoon SH, Nam JW, Seong JK, Oh GT, Randolph GJ, Artyomov MN, Cheong C, Choi JH (2018) Transcriptome analysis reveals nonfoamy rather than foamy plaque macrophages are proinflammatory in atherosclerotic murine models. Circ Res 123(10):1127–1142. https://doi.org/10.1161/CIRCRESAHA.118.312804

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Lin JD, Nishi H, Poles J, Niu X, McCauley C, Rahman K, Brown EJ, Yeung ST, Vozhilla N, Weinstock A, Ramsey SA, Fisher EA, Loke P (2019) Single-cell analysis of fate-mapped macrophages reveals heterogeneity, including stem-like properties, during atherosclerosis progression and regression. JCI Insight 4(4). https://doi.org/10.1172/jci.insight.124574

  142. Pan H, Xue C, Auerbach BJ, Fan J, Bashore AC, Cui J, Yang DY, Trignano SB, Liu W, Shi J, Ihuegbu CO, Bush EC, Worley J, Vlahos L, Laise P, Solomon RA, Connolly ES, Califano A, Sims PA, Zhang H, Li M, Reilly MP (2020) Single-cell genomics reveals a novel cell state during smooth muscle cell phenotypic switching and potential therapeutic targets for atherosclerosis in mouse and human. Circulation 142(21):2060–2075. https://doi.org/10.1161/CIRCULATIONAHA.120.048378

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by National Natural Science Foundation of China (No. 82090044 to B.H, No.81820108010 to B.H, No.82001271 to J.H.W.) and National Key R&D Program of China (No. 2018YFC1312200).

Author information

Authors and Affiliations

Authors

Contributions

Yu-xiao Liu and Pei-zhe Yuan had the idea and performed the literature search. Jie-hong Wu and Bo Hu drafted and revised the article.

Corresponding authors

Correspondence to Jie-hong Wu or Bo Hu.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Yx., Yuan, Pz., Wu, Jh. et al. Lipid accumulation and novel insight into vascular smooth muscle cells in atherosclerosis. J Mol Med 99, 1511–1526 (2021). https://doi.org/10.1007/s00109-021-02109-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-021-02109-8

Keywords

Navigation