Cellular Basis of Atherosclerosis

  • Marc Fisher


Atherosclerosis, involving the large extracranial arteries, is a common substrate for the development of ischemic stroke in the anterior or posterior cerebral circulations. Additionally, intracranial atherosclerosis may also be causally related to ischemic stroke, especially in non-white populations.1 Many patients with large-vessel cerebral atherosclerosis harbor such lesions in other critical vessels, such as the coronary arteries, aorta, and lower extremity vessels. 2 Atherosclerosis is a ubiq- uitous problem in industrialized society, and although mortality secondary to acute myocardial infarction (MI) and ischemic stroke have declined, these twin scourges still cause over 600,000 deaths annually in the United States. 3,4 Atherogenesis is an insidious process that develops over decades and may go undetected or unrecognized until the appearance of a devastating MI or stroke. Much has been learned about the nature and pathogenesis of atherosclerosis.5


Smooth Muscle Cell Ischemic Stroke Wall Shear Stress Atherosclerotic Plaque Arterial Wall 
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  1. 1.
    Caplan LR, Gorelick PB, Hier DB. Race, sex and occlusive vascular disease: a review. Stroke. 1984; 17:648–655.Google Scholar
  2. 2.
    Hertzer NR, Young Jr, Beven EG, et al. Coronary angiography in 506 patients with extracranial cerebrovascular disease. Arch Int Med. 1985; 145:849–852.Google Scholar
  3. 3.
    Arteriosclerosis. Report of the working group on arteriosclerosis of the National Heart, Lung and Blood Institute, vol 2. Washington, DC: U.S. Department of Health and Human Services; 1981.Google Scholar
  4. 4.
    Gillum RE Cerebrovascular disease morbidity in the United States, 1970–1983: age, sex, region, and vascular surgery. Stroke. 1986;17:656–661.PubMedGoogle Scholar
  5. 5.
    Ross R. The pathogenesis of atherosclerosis: an update. N Engl J Med. 1986;314:488–500.PubMedGoogle Scholar
  6. 6.
    Long ER. The development of our knowledge of arteriosclerosis. In: Cowdry EV, ed. Arteriosclerosis: A survey of the Problem. New York, NY: Mac-millan; 1933: pp 19–52.Google Scholar
  7. 7.
    Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAMA. 1912;58:2015–2020.Google Scholar
  8. 8.
    Fisher CM. Occlusion of the internal carotid artery. Arch Neurol Psychiatry. 1951;65:346–377.Google Scholar
  9. 9.
    Fisher CM. Observations of the fundus oculi in the transient monocular blindness. Neurology. 1959;9: 333–347.PubMedGoogle Scholar
  10. 10.
    Fisher CM, Gore I, Okabe N, et al. Atherosclerosis of the carotid and vertebral arteries: extracranial and intracranial. J Neuropathol Exp Neurol. 1965; 24:455–476.Google Scholar
  11. 11.
    Stary HC. Evolution and progression of atherosclerosis in the coronary arteries of children and adults. In: Bates SR, Gangloff EC, eds. Atherogene-sis and Aging. New York, NY: Springer-Verlag; 1987: pp 20–36.Google Scholar
  12. 12.
    Azel NM, Ball RY, Waldman H, et al. Identification of macrophages and smooth muscle cells in human atherosclerosis using monoclonal antibodies. J Pathol 1985; 146:197–201.Google Scholar
  13. 13.
    Ross R, Wight TN, Strandness E, et al. Human atherosclerosis: I. Cell constitution and characteristics of advanced lesions of the superficial femoral artery. Am J Pathol. 1984;114:79–93.PubMedGoogle Scholar
  14. 14.
    Barger CA, Becuwkes R, Lainey LL, et al. Hypothesis: vasa vasorum and neovascularization of human coronary arteries. N Engl J Med. 1984;310:175–177.PubMedGoogle Scholar
  15. 15.
    McGill HC. The pathogenesis of atherosclerosis. Clin Chem. 1988;34:B33-B39.PubMedGoogle Scholar
  16. 16.
    McGill HC. Persistent problems in the pathogenesis of atherosclerosis. Arteriosclerosis. 1984;4: 443–451.PubMedGoogle Scholar
  17. 17.
    Faggiotto A, Ross R. Studies of hypercholesterolemia in the non-human primate: II. Fatty streak conversion to fibrous plaque. Arteriosclerosis. 1984;4: 341–356.PubMedGoogle Scholar
  18. 18.
    Montenegro MR, Eggen DA. Topography of atherosclerosis in the coronary arteries. Lab Invest. 1968; 18:586–593.PubMedGoogle Scholar
  19. 19.
    Geer JC, McGill HC, Robertson WB, et al. Histologic characteristics of coronary artery fatty streaks. Lab Invest. 1960;18:565–570.Google Scholar
  20. 20.
    Deewood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med. 1980;303:897–902.Google Scholar
  21. 21.
    Falk E. Plaque rupture with severe pre-existing stenosis precipitates coronary thrombosis. Br Heart J. 1983;50:127–134.PubMedGoogle Scholar
  22. 22.
    Davies MJ, Thomas AC. Plaque Assuring: the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J. 1985;53:363–373.PubMedGoogle Scholar
  23. 23.
    Imparato AM, Riles TS, Mintzer R, et al. The importance of hemorrhage in the relationship between gross morphologic and cerebral symptoms in 376 carotid artery plaques. Ann Surg. 1983; 197:195–203.PubMedGoogle Scholar
  24. 24.
    Persson AV. Intraplaque hemorrhage. Surg Clin North Am. 1986;66:415–420.PubMedGoogle Scholar
  25. 25.
    Lennihan L, Kupsky WJ, Mohr JP, et al. Lack of association between carotid plaque hematoma and ischemic cerebral symptoms. Stroke. 1987; 18: 879–881.PubMedGoogle Scholar
  26. 26.
    Bassiouny HJ, Davis H, Massama N, et al. Critical carotid stenosis: morphologic and chemical similarity between symptomatic and asymptomatic plaques. J Vase Surg. 1989;9:202–212.Google Scholar
  27. 27.
    Fisher CM, Ojemann RG. A clinico-pathologic study of endarterectomy plaques. Rev Neurol. 1986;142:573–589.PubMedGoogle Scholar
  28. 28.
    Fisher M, Blumenfeld AM, Smith TW. The importance of carotid artery plaque disruption and hemorrhage. Arch Neurol. 1987;44:1086–1089.PubMedGoogle Scholar
  29. 29.
    Schwartz CJ, Yalente AJ, Kelley JL, et al. Thrombosis and the development of atherosclerosis. Semin Thromb Hemost. 1988;14:189–195.PubMedGoogle Scholar
  30. 30.
    Vesselinovitch D. Animal models and the study of atherosclerosis. Arch Pathol Lab Med. 1988; 112: 1011–1017.PubMedGoogle Scholar
  31. 31.
    Gerrity RG, Naito HK, Richardson M, et al. Dietary induced atherogenesis in swine. Am J Pathol. 1979;95:775–792.PubMedGoogle Scholar
  32. 32.
    Munro MJ, Cotran RS. The pathogenesis of atherosclerosis: atherogenesis and inflammation. Lab Invest. 1988;58:249–301.PubMedGoogle Scholar
  33. 33.
    Ross R, Glomset JA. The pathogenesis of atherosclerosis. N Engl J Med. 1976;295:369–377, 420–425.PubMedGoogle Scholar
  34. 34.
    Duel TF. Polypeptide growth factors: roles in normal and abnormal cell growth. Ann Rev Cell Biol. 1987;3:443–492.Google Scholar
  35. 35.
    Mitchinson MJ, Ball RY. Macrophages and atherogenesis. Lancet. 1987;2:146–149.PubMedGoogle Scholar
  36. 36.
    Faggiotto A, Ross R, Harker L. Studies of hypercholesterolemia in the non-human primate: I. Changes that lead to fatty streak formation. Arteriosclerosis. 1984;4:323–340.PubMedGoogle Scholar
  37. 37.
    Steinberg D. Lipoproteins and the pathogenesis of atherosclerosis. Circulation. 1987;76:508–514.PubMedGoogle Scholar
  38. 38.
    Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983;52:223–261.PubMedGoogle Scholar
  39. 39.
    Mazzone T, Jensen M, Chait A. Human arterial wall cells release factors that are chemotactic for monocytes. Proc Natl Acad Sci. 1983;80:5094–5097.PubMedGoogle Scholar
  40. 40.
    Nathan CF. Secretory products of macrophages. J Clin Invest. 1987;79:319–326.PubMedGoogle Scholar
  41. 41.
    Jonasson L, Holm J, Skalli O, et al. Regional accumulation of T cells, macrophages, and smooth muscle cells in human atherosclerotic plaques. Arteriosclerosis. 1986;6:131–138.PubMedGoogle Scholar
  42. 42.
    Cathcart MK, Morel DW, Chisholm GM. Monocytes and neutrophils oxidize low density lipopro-trotein making it cytotoxic. J Leukocyte Biol. 1985; 38:341–350.PubMedGoogle Scholar
  43. 43.
    Yatsu FM, Alam R, Alam S. Scavenger activity in monocyte-derived macrophages from athero-thrombotic strokes. Stroke. 1986;17:709–713.PubMedGoogle Scholar
  44. 44.
    Jaffe EA. Cell biology of endothelial cells. Human Pathol. 1987;18:234–239.Google Scholar
  45. 45.
    Morel DW, Dicorleto PE, Chisholm GM. Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation. Arteriosclerosis. 1984;4:357–364.PubMedGoogle Scholar
  46. 46.
    Ross R, Raines EW, Bowen-Pope DF. The biology of platelet-derived growth factor. Cell. 1986;46: 155–164.PubMedGoogle Scholar
  47. 47.
    Castellot JJ, Addonzio ML, Rosenberg R, et al. Cultured endothelial cells produce a heparin-like inhibitor of smooth muscle cell growth. J Cell Biol. 1981;90:372–379.PubMedGoogle Scholar
  48. 48.
    Campbell GR, Chamley-Campbell JH. The cellular pathology of atherosclerosis. Pathology. 1981; 13: 423–440.PubMedGoogle Scholar
  49. 49.
    Libby P, Warner SJC, Salomon RN, et al. Production of platelet derived growth factor-like mitogen by smooth muscle cells from human atheroma. N Engl J Med. 1988;318:1493–1498.PubMedGoogle Scholar
  50. 50.
    Goldberg ID, Stemerman MB, Handin RI. Vascular permeation of platelet factor 4 after endothelial injury. Science. 1980;209:611–612.PubMedGoogle Scholar
  51. 51.
    Ross R, Glomset JA, Kariya B, et al. A platelet-derived serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci. 1974;71:1207–1210.PubMedGoogle Scholar
  52. 52.
    Ross R. Platelet-derived growth factor. Lancet. 1989;1:1179–1182.PubMedGoogle Scholar
  53. 53.
    Klagsbrun M, Edelman ER. Biological and biochemical properties of fibroblast growth factors. Arteriosclerosis. 1989;9:269–278.PubMedGoogle Scholar
  54. 54.
    Habenicht A, Goerig M, Grulich J, et al. Human platelet derived growth factor stimulates prostaglandin synthesis by activation and de novo synthesis of cyclooxygenase. J Clin Invest. 1985 ;75:1381–1387.PubMedGoogle Scholar
  55. 55.
    Doolittle RF, Hunkapiller MW, Hood LE, et al. Simian sarcoma virus one gene, v-sis is derived from a tse gene (or genes) encoding a platelet-derived growth factor. Science. 1983;221:275–277.PubMedGoogle Scholar
  56. 56.
    Solberg LA, Strong JP., Risk factors and atherosclerotic lesions: A review of autopsy studies. Arteriosclerosis. 1983;3:187–198.PubMedGoogle Scholar
  57. 57.
    Glagov S, Zarins C, Giddens DP, et al. Hemodynamics and atherosclerosis. Arch Pathol Lab Med. 1988;112:1018–1031.PubMedGoogle Scholar
  58. 58.
    Friedman MH, Hutchins GM, Bargeron CR, et al. Correlation between intimal thickness and fluid shear in human arteries. Arteriosclerosis. 1981;39: 425–431.Google Scholar
  59. 59.
    Zarins CK, Giddens DP, Bharadavaj BK, et al. Carotid bifurcation atherosclerosis: quantitation of plaque localization with flow velocity profiles and wall shear stress. Circ Res. 1983;53:502–514.PubMedGoogle Scholar
  60. 60.
    Reneman RS, van Merode T, Smeets FAM, et al. Velocity patterns and vessel wall properties in the carotid artery bulb in man —their relationship to atherosclerosis. In: Hennerici M, Sitzer G, Weger HD, eds. Carotid Artery Plaques. Basel; Karger; 1988: pp 143–162.Google Scholar
  61. 61.
    Lewis JC, Taylor RG, Normal BS, et al. Endothelial surface characteristics in pigeon coronary atherosclerosis. Lab Invest. 1982;46:133–138.Google Scholar
  62. 62.
    Nerum RM, Levesque MJ, Sato M. Mechanical properties of endothelial cells. Biorrheology. 1986; 23:230.Google Scholar
  63. 63.
    Ku DN, Giddens DP. Pulsatile flow in a model carotid bifurcation. Arteriosclerosis. 1983;3:31–39.PubMedGoogle Scholar
  64. 64.
    Gerrity RG, Goss JA, Soby L. Control of monocyte recruitment by chemotactic factor(s) in lesion-prone areas of swine aorta. Arteriosclerosis. 1985; 5:55–66.PubMedGoogle Scholar
  65. 65.
    Glagov S, Weisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987;316:1371–1375.PubMedGoogle Scholar
  66. 66.
    Guyton JR, Hotley CJ. Flow restriction in one carotid artery in juvenile rats inhibits growth of arterial diameter. Am J Physiol. 1985;248:H540–546.PubMedGoogle Scholar
  67. 67.
    Roberts WC. Factors linking cholesterol to atherosclerotic plaques. Am J Cardiol. 1988;62:495–499.PubMedGoogle Scholar
  68. 68.
    Yatsu FM, Fisher M. Atherosclerosis: current concepts on pathogenesis and interventional strategies. Ann Neurol. 1989;26:3–12.PubMedGoogle Scholar
  69. 69.
    Lewis JC, Taylor RG, Jones ND, et al. Endothelial surface characteristics in pigeon coronary atherosclerosis. Lab Invest. 1982;46:123–138.PubMedGoogle Scholar
  70. 70.
    Steinberg D, Parthasarathy S, Carew TE, et al. Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. TV Engl J Med. 1989;320:915–924.Google Scholar
  71. 71.
    Mosel DW, DiCarleto PE, Chisolm GM. Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation. Arteriosclerosis. 1984;4:357–364.Google Scholar
  72. 72.
    Hiramatsu K, Rosen H, Heinecke JW, et al. Superoxide initiates oxidation of low-density lipoproteins by human monocytes. Arteriosclerosis. 1987; 7:55–60.PubMedGoogle Scholar
  73. 73.
    Palinski W, Rosenfeld ME, Yla-Herttualla, et al. Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci USA. 1984; 86:1372–1376.Google Scholar
  74. 74.
    Quinn MT, Parthasarathy S, Fong LG, et al. Oxidatively modified low density lipoproteins: a potential role in recruitment and retention of monocyte/macrophages during atherogenesis. Proc Natl Acad Sci USA. 1987;84:2995–2998.PubMedGoogle Scholar
  75. 75.
    Kita T, Nagano Y, Yokode M, et al. Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipedimic rabbit, an animal model for familial hypercholesterolemia. Proc Natl Acad Sci USA. 1987;84:5928–5931.PubMedGoogle Scholar
  76. 76.
    Fisher M, Leaf A, Levine PH. N-3 fatty acids and cellular aspects of atherosclerosis. Arch Int Med. 1989;149:1726–1728.Google Scholar
  77. 77.
    Berry CL, Greenwald SE. Effect of hypertension on the static mechanical properties and chemical composition of the rat aorta. Cardiovasc Res. 1976; 10:437–451.PubMedGoogle Scholar
  78. 78.
    Sacks AM. The vasa vasorum as a link between hypertension and arteriosclerosis. Angiology. 1975; 26:385–390.Google Scholar
  79. 79.
    Fitzgerald GA, Oates JA, Nowak J. Cigarette smoking and hemostatic function. Am Heart J. 1981; 115:267–271.Google Scholar
  80. 80.
    Seiffert GF, Keown K, Moore SW. Pathologic effects of tobacco smoke inhalation on arterial intima. Surg Forum. 1981;32:353–359.Google Scholar
  81. 81.
    Mjos OD. Lipid effects of smoking. Am Heart J. 1988;115:267–271.Google Scholar
  82. 82.
    National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Report. Arch Int Med. 1988;148:36–69.Google Scholar
  83. 83.
    Taguchi J, Freis ED. Partial reduction of blood pressure and prevention of complications of hypertension. N Engl J Med. 1974;291:329–331.PubMedGoogle Scholar
  84. 84.
    Shinton R, Beevers G. Meta-analysis of relation between cigarette smoking and stroke. Br Med J. 1989;298:789–794.Google Scholar
  85. 85.
    Goodnight SH, Fisher M, Fitzgerald GA, et al. Assessment of the therapeutic use of dietary fish oil in atherosclerotic vascular disease and thrombosis. Chest. 1989;95:19S-25S.PubMedGoogle Scholar
  86. 86.
    Dehmer GF, Popma JJ, Van den Berg EK, et al. Reduction in the rate of early restenosis after coronary angioplasty by a diet supplemented with n-3 fatty acids. N Engl J Med. 1988;319:733–740.PubMedGoogle Scholar
  87. 87.
    Weiner BH, Ockene IS, Levine PH, et al. Inhibition of atherosclerosis by cod liver oil in a hyper-lipidemic swine model. N Engl J Med. 1986;315: 841–846.PubMedGoogle Scholar
  88. 88.
    Kim DN, Ho HT, Lawrence DA, et al. Modification of lipoprotein patterns and retardation of atherogenesis by a fish oil supplement to a hyper-lipidemic diet for swine. Atherosclerosis. 1989;76: 35–54.PubMedGoogle Scholar
  89. 89.
    Davis HR, Bridenstine RT, Vesselinovitch D, et al. Fish oil inhibits development of atherosclerosis in rhesus monkeys. Arteriosclerosis. 1987;7:441–449.PubMedGoogle Scholar
  90. 90.
    Soltys PA, Massone T, Wissler RW. Effects of feeding of fish oil on the properties of lipoproteins isolated from rhesus monkeys consuming an atherogenic diet. Atherosclerosis. 1989;76:103–115.PubMedGoogle Scholar
  91. 91.
    Hollander W, Hong S, Kirkpatrick BJ, et al. Differential effects of fish oil supplements on atherosclerosis. Circulation 70. 1987; (suppl IV):313.Google Scholar
  92. 92.
    Harris WJ, Dujone CA, Zucker M, et al. Effects of a low saturated fat, low cholesterol fish oil supplement in hypertriglyceridemic patients. Ann Int Med. 1988;109:465–470.PubMedGoogle Scholar
  93. 93.
    Knapp HR, Reilly IA, Allessandrini P, et al. In vivo indexes of platelet and vascular function during fish oil administration in patients with atherosclerosis. N Engl J Med. 1986;314:939–942.Google Scholar
  94. 94.
    Schmidt EB, Pedersen JO, Ekelund S, et al. Cod liver oil inhibits neutrophil and monocyte Chemotaxis in healthy males. Atherosclerosis. 1989;77:53–57.PubMedGoogle Scholar
  95. 95.
    Fox PL, DiCarleto PE. Fish oil inhibits endothelial cell production of a platelet-derived growth factorlike protein. Science. 1988;241:453–456.PubMedGoogle Scholar
  96. 96.
    Shimokawa H, Vanhoutte PM. Dietary ω-3 polyunsaturated fatty acids and endothelium-depen-dent relaxations in porcine coronary arteries. Am J Physiol. 1989;256:H968-H973.PubMedGoogle Scholar
  97. 97.
    Henry PD. Calcium antagonists as antiatherogenic agents. Ann N Y Acad Sci. 1988;522:411–419.PubMedGoogle Scholar
  98. 98.
    Vesselinovitch DJ, Mullan JF, Wissler RW, et al. Carotid atherogenesis inhibited by sympathectomy, propranolol and nifedipine in rhesus monkeys. Arteriosclerosis. 1986;6:516a.Google Scholar
  99. 99.
    Parmley WW, Blumlein S, Sievers R. Modification of experimental atherosclerosis by calcium channel blockers. Am J Cardiol. 1985;55:165B-171B.PubMedGoogle Scholar
  100. 100.
    Nakao J, Hideki I, Doyama T, et al. Calcium dependency of aortic smooth muscle cell migration induced by 12-L-hydroxy-5.8, 10, 14-eico-statetraenoic acid. Atherosclerosis. 1983;46:309–319.PubMedGoogle Scholar
  101. 101.
    Van Valen RG, Deacon RW, Farley C, et al. Antiproliferative effect of calcium channel blockers PN 200–110 and PY 108–068 in the rat carotid model of balloon catheterization. Fed Proc. 1985; 44:737.Google Scholar
  102. 102.
    Clones AW, Karnovsky MJ. Suppression by heparin of smooth muscle cell proliferation in injured arteries. Nature. 1977;256:625–626.Google Scholar
  103. 103.
    Castellot JJ, Beeler DL, Rosenberg RD, et al. Structural determinants of the capacity of heparin to inhibit the proliferation of vascular smooth muscle cells. J Cell Physiol. 1984;120:315–320.PubMedGoogle Scholar
  104. 104.
    Castellot JJ, Favreau LV, Karnovsky MJ, et al. Inhibition of vascular smooth muscle cell growth by endothelial cell-derived heparin—possible role of platelet endoglycosidase. J Biol Chem. 1982;257: 11256–11260.PubMedGoogle Scholar

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  • Marc Fisher

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