Endothelial Dysfunction and the Pathogenesis of Atherosclerosis

  • Michael A. GimbroneJr


Vascular endothelium is a structurally simple but functionally complex tissue, the integrity of which is essential to the health of the arterial wall. Since the classical theories of Rokitansky and Virchow, various roles have been ascribed to endothelium in the atherosclerotic process, but only recently have many relevant aspects of its biology been appreciated. In part this is due to the development of new experimental tools, but more importantly it reflects a renewed interest in the functional capabilities of vascular cells, their mutual interactions, and the potential consequences of their dysfunction.


Human Vascular Endothelial Cell Prostaglandin Endoperoxide Bovine Endothelial Cell Aortic Endothelium Medial Smooth Muscle Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Alonso DR, Starek PK, Minick CR (1977) Studies on the pathogenesis of athero-arteriosclerosis induced in rabbit cardiac allografts by the synergy of graft rejection and hyperchoiesterolemia. Amer J Pathol 87: 415Google Scholar
  2. Baumgartner HR (1974) In: Deutsch E, Brinkhous KM, Lechner K, Hinnom S (eds) Thrombosis: Pathogenesis and Clinical Trials. Schattauer-Verlag, Stuttgart (p 91)Google Scholar
  3. Becker CG, Harpel PC (1976) Alpha2-macroglobulin on human vascular endothe-lium. J Exp Med 144: 1PubMedCrossRefGoogle Scholar
  4. Björkerud S, Bondjer G (1971) Arterial repair and atherosclerosis after mechanical injury, I. Permeability and light microscopic characteristics of endothelium in non-atherosclerotic and atherosclerotic lesions. Atherosclerosis 13: 355PubMedCrossRefGoogle Scholar
  5. Birdwell CR, Gospodarowicz D, Nicolson GL (1978) Identification, localization, and role of fibronectin in cultured bovine endothelial cells, Proc Natl Acad Sci USA 75: 3273PubMedCrossRefGoogle Scholar
  6. Booyse FM, Quarfoot AJ, Bell S, Fass DN, Lewis JC, Mann KG, Bowie JW (1977) Cultured aortic endothelial cells from pigs with von Willebrand disease: In vitro model for studying the molecular defect(s) of the disease, Proc Natl Acad Sci USA 74: 5702PubMedCrossRefGoogle Scholar
  7. Buonassisi V, Roo M (1975) Enzymatic degradation of heparin related muco-polysaccharides from the surface of endothelial cell cultures. Biochim Biophys Acta 383: 1CrossRefGoogle Scholar
  8. Caplan BA, Schwartz CJ (1973) Increased endothelial cell turnover in areas of in vivo evans blue uptake in the pig aorta. Atherosclerosis 17: 401PubMedCrossRefGoogle Scholar
  9. Coetzee GA, Stein O, Stei Y (1979) Uptake and degradation of low density lipoproteins (LDL) by confluent, contact-inhibited bovine and human endothelial cells exposed to physiological concentrations of LDL. Atherosclerosis 33: 425PubMedCrossRefGoogle Scholar
  10. Curwen KD, Gimbrone MA, Jr, Handin RI (1979) In vitro studies of thrombore-sistance: The role of prostacyclin (PGI2) in platelet adhesion to cultured normal and virally transformed human vascular endothelial cells. Lab Invest (in press)Google Scholar
  11. Curwen K, Smit S (1977) Aortic glycosaminoglycans in atherosclerosis susceptible and resistant pigeons. Exp Mol Pathol 27: 121PubMedCrossRefGoogle Scholar
  12. Davies PF, Reidy MA, Goode TB, Bowyer DE (1976) Scanning electron microscopy in the evaluation of endothelial integrity of the fatty lesion in atherosclerosis. Atherosclerosis 25: 125PubMedCrossRefGoogle Scholar
  13. Davies PF, Ros R (1978) Mediation of pinocytosis in cultured arterial smooth muscle and endothelial cells by platelet-derived growth factor. J Cell Biol 79: 663PubMedCrossRefGoogle Scholar
  14. DeForrest JM, Hollis TM (1978) Shear stress and aortic histamine synthesis. Amer J Physiol 234(6): H701PubMedGoogle Scholar
  15. Dicorleto PE, Zilversmit DB (1975) Lipoprotein lipase activity in bovine aorta. Proc Soc Exp Biol Med 148: 1101PubMedGoogle Scholar
  16. Eisenstein R, Schumacher B, Matijevitc B (1979) Intrinsic regulators of arterial cell growth. Fed Proc 38(3): 1075Google Scholar
  17. Fishman JA, Ryan FB, Karnovsky MJ (1975) Endothelial regeneration in the rat carotid artery and the significance of endothelial denudation in the pathogenesis of myointimal thickening. Lab Invest 32: 339PubMedGoogle Scholar
  18. Fuster V, Bowie EJW, Lewis JC, Fass DN, Owen CA, Jr, Brown AL (1978) Resistance to arteriosclerosis in pigs with von Willebrand’ s disease. J Clin Invest 61: 722PubMedCrossRefGoogle Scholar
  19. Gamse G, Fromme HG, Kress H (1978) Metabolism of sulfated glycosaminoglycans in cultured endothelial cells and smooth muscle cells from bovine aorta. Biochim Biophys Acta 544: 514PubMedCrossRefGoogle Scholar
  20. Gaynor E, Bouvier CA, Spaet TH (1970) Vascular lesions: possible pathogenetic basis of the generalized Shartzman reaction. Science 170: 986PubMedCrossRefGoogle Scholar
  21. Gerrity RG, Naito HK, Richardson M, Schwartz CJ (1979) Dietary induced atherogenesis in swine: Morphology of the intima in prelesion stages. Amer J Pathol 95: 775Google Scholar
  22. Gerrity RG, Richardson M, Caplan BA, Cade JF, Hirsh J, Schwartz CJ (1976) Endotoxin-induced vascular endothelial injury and repair II. Focal injury, en face morphology, 3H thymidine uptake and circulating endothelial cells in the dog. Exp Mol Pathol 24: 59PubMedCrossRefGoogle Scholar
  23. Gimbrone MA, Jr (1976) Culture of vascular endothelium. In: Spaet TH (ed) Progress in hemostasis and thrombosis Vol. III. Grune & Stratton, New YorkGoogle Scholar
  24. Gimbrone MA, Jr (1977) Culture of vascular endothelium and atherosclerosis. In: Brinkley BR, Porter KR (eds) International cell biology 1976-1977. The Rockefeller University PressGoogle Scholar
  25. Gimbrone MA, Jr (1980) Vascular endothelium and atherosclerosis. In: Moore S (ed) Arteriosclerosis. Marcel Dekker, New York (in press)Google Scholar
  26. Gimbrone MA, Jr. Alexander RW (1977) Prostaglandin production by vascular endothelial and smooth muscle cells in culture. In: Silver MJ, Kocsis JJ (eds) Prostaglandins in hematology. Sprectrum Publications, New YorkGoogle Scholar
  27. Gimbrone MA, Jr, Cotran RS, Folkma J (1974) Human vascular endothelial cells in culture: Growth and DNA synthesis, J Cell Biol Biol 60: 673CrossRefGoogle Scholar
  28. Goode TB, Davies PF, Reidy MA, Bowyer DE (1977) Aortic endothelial cell morphology observed in situ by scanning electron microscopy during atherogenesis in the rabbit. Atherosclerosis 27: 235PubMedCrossRefGoogle Scholar
  29. Habliston DL, Ryan US, Ryan JW (1978) Endothelial cells degrade adenosine-5′-diphosphate. J Cell Biol 78: 206aGoogle Scholar
  30. Hamberg M, Svensson J, Samuelsso B (1974) Prostaglandin endoperoxides. A new concept concerning the mode of action and release of prostaglandins. Proc Natl Acad Sci USA 71: 3824PubMedCrossRefGoogle Scholar
  31. Harker LA, Ross R, Slichter SJ, Scott CR (1976) Homocystine-induced arteriosclerosis: The role of endothelial cell injury and platelet response in its genesis. J Clin Invest 58: 731PubMedCrossRefGoogle Scholar
  32. Haudenschild CC, Zahniser D, Folkman J, Klagsbru M (1976) Human vascular endothelial cells in culture: Lack of response to serum growth factors. Exp Cell Res 98: 175PubMedCrossRefGoogle Scholar
  33. Hial V, Gimbrone, MA, Jr, Peyton MP, Wilcox GM, Pisano JJ (1979) Angiotensin metabolism by cultured human vascular endothelial and smooth muscle cells. Microvascular Res 17: 314CrossRefGoogle Scholar
  34. Hollis TM, Rosen LA (1972) Histidine decarboxylase activity of bovine aortic endothelium and intima-media. Proc Soc Exp Biol Med 141: 978PubMedGoogle Scholar
  35. Howard VV, Macarak EJ, Gunson D, Kefalides NA (1976) Characterization of the collagen synthesized by endothelial cells in culture. Proc Natl Acad Sci USA 73: 2361PubMedCrossRefGoogle Scholar
  36. Iverius PH (1972) The interaction between human and plasma lipoproteins and connective tissue glycosaminoglycans. J Biol Chem 247: 2607PubMedGoogle Scholar
  37. Jaffe EA, Minick CR, Adelman B, Becker CG, Nachma R (1976) Synthesis of basement collagen by cultured human endothelial cells. J Exp Med 144: 209PubMedCrossRefGoogle Scholar
  38. Jaffe EA, Mosher DF (1978) Synthesis of fibronectin by cultured human endothelial cells. J Exp Med 147: 1779PubMedCrossRefGoogle Scholar
  39. Jaffe EA, Hoyer LW, Nachman RL (1974) Synthesis of von Willebrand factor by cultured human endothelial cells. Proc Natl Acad Sci USA 71: 1906PubMedCrossRefGoogle Scholar
  40. Johnson AR, Erdos EG (1977) Metabolism of vasoactive peptides by human endothelial cells in culture. J Clin Invest 59: 684PubMedCrossRefGoogle Scholar
  41. Lewis JC, Kottke BA (1977) Endothelial damage and thrombocyte adhesion in pigeon atherosclerosis. Science 196: 1007PubMedCrossRefGoogle Scholar
  42. Loskutoff DJ, Edgington TS (1977) Synthesis of a fibrolytic activator and inhibitor by endothelial cells. Proc Natl Acad Sci USA 74: 3903PubMedCrossRefGoogle Scholar
  43. Macarak EJ, Kirby E, Kirk T, Kefalides NA (1978) Synthesis of cold-insoluble globulin by cultured calf endothelial cells. Proc Natl Acad Sci USA 75: 2621PubMedCrossRefGoogle Scholar
  44. Majn G (1965) Ultrastructure of the,vascular membrane. Chapter 64 In: Hamilton WF, Dow P (eds) Handbook of physiology, Section 2: Circulation Vol II. American Physiological Society, Washington, D.C.Google Scholar
  45. Majno G, Jori I (1978) Endothelium 1977: A review. In: Chandler AB et al (eds) The throiribotic process in atherogenesis. Plenum Press, New YorkGoogle Scholar
  46. Martin BM, Baldwin WM, Gimbrone MA, Jr, Unanue ER, Cotran RS (1979) Macrophage factor(s): stimulation of cell growth in vitro and new blood vessels in vivo. J Cell Biol 83: 376aGoogle Scholar
  47. Maynard JR, Heckman CA, Pitlick FA, Nemerso Y (1975) Association of tissue factor activity with the surface of cultured cells. J Clin Invest 55: 814PubMedCrossRefGoogle Scholar
  48. Minick CR, Stemerman MB, Insull W, Jr (1977) Effect of regenerated endothelium on lipid accumulation in the arterial wall. Proc Natl Acad Sci USA 74(4): 1742CrossRefGoogle Scholar
  49. Moncada S, Gryglewski R, Bunting S, Vane JR (19 76) An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature 263: 663CrossRefGoogle Scholar
  50. Moncada S, Vane JR (1979) Arachidonic acid metabolites and the interactions between platelets and blood-vessel walls. N Engl J Med 300: 1142PubMedCrossRefGoogle Scholar
  51. Moor S (1973) Thromboatherosclerosis in normolipemic rabbits: A result of continued endothelial damage. Lab Invest 29: 478Google Scholar
  52. Nelson E, Gertz GD, Forbes MS, Rennels ML, Heald FP, Kahn MA, Farber TM, Miller E, Husain MM, Earl FL (1976) Endothelial lesions in the aorta of egg yolk-fed miniature swine: A study by scanning and transmission electron microscopy. Exp Mol Pathol 25: 208PubMedCrossRefGoogle Scholar
  53. Olivecrona T, Bengtsson G, Hook M, Luidoh U (1976) Physiologic implications of the interaction between lipoprotein lipase and some sulfated glycos-aminoglycans. In: Greten H (ed) Lipoprotein metabolism. Springer, BerlinGoogle Scholar
  54. Pearson JD, Gordon JL (1979) Vascular endothelial and smooth muscle cells in culture selectively release adenine nucleotides. Nature 281: 384PubMedCrossRefGoogle Scholar
  55. Pelikan P, Gimbrone MA, Jr, Cotran RS (1979) Distribution and movement of anionic cell surface sites in cultured human vascular endothelial cells. Atherosclerosis 32: 69PubMedCrossRefGoogle Scholar
  56. Polverini PJ, Cotran RS, Gimbrone MA, Jr, Unanue ER (1977) Activated macrophages induce vascular proliferation. Nature 269: 804PubMedCrossRefGoogle Scholar
  57. Poole JCF, Sanders AG, Florey HM (1958) The regenration of aortic endothelium. J Pathol Bacteriol 75: 133PubMedCrossRefGoogle Scholar
  58. Reidy MA, Bowyer DE (19 78) Distortion of endothelial repair. The effect of hyperchoiesterolaemia on regeneration of aortic endothelium following injury by endotoxin. Atherosclerosis 29: 459CrossRefGoogle Scholar
  59. Ross R, Glomset JA (19 76) Medical Progress: The pathogenesis of atherosclerosis. N Engl J Med 295: 369CrossRefGoogle Scholar
  60. Ross R, Glomset J, Kariya B, Harke L (1974) A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Natl Acad Sci USA 71: 1207PubMedCrossRefGoogle Scholar
  61. Ross R, Harke L (1976) Hyperlipidemia and atherosclerosis: Chronic hyper-lipidemia initiates and maintains lesions by endothelial cell desquamation and lipid accumulation. Science 193: 1094PubMedCrossRefGoogle Scholar
  62. Sakariassen KS, Bolhuis PA, Sixma JJ (1979) Human blood platelet adhesion to artery subendothelium is mediated by factor VIII — von Willebrand factor bound to the subendothelium. Nature 279: 636PubMedCrossRefGoogle Scholar
  63. Schwartz SM, Benditt EP (19 73) Cell replication in the aortic endothelium: A new method for study of the problem. Lab Invest 28: 699Google Scholar
  64. Schwartz SM, Benditt EP (19 77) Aortic endothelial cell replication I. Effects of age and hypertension in the rat. Circ Res 41: 248Google Scholar
  65. Schwartz SM, Haudenschild CC, Eddy EM (1978) Endothelial regeneration I. Quantitative analysis of intial stages of endothelial regeneration in rat aortic intima. Lab Invest 38: 568PubMedGoogle Scholar
  66. Schwartz SM, Stemerman MB, Benditt EP (1975) The aortic intima II. Repair of the aortic lining after mechcuu-cal denudation. Amer J Pathol 81: 15Google Scholar
  67. Scow RO, Blanchette-Mackie EJ, Smith LC (1976) Role of capillary endothelium in the clearnace of chylomicrons. A model for lipid transport from blood by lateral diffusion in cell membranes. Circ Res 39: 149PubMedGoogle Scholar
  68. Seiden SC, III, Schwartz SM (19 79) Cytochalasin B inhibition of endothe-lial proliferation at wound edges in vitro. J Cell Biol 81: 348CrossRefGoogle Scholar
  69. Sholley MM, Gimbrone MA., Jr, Cotran RS (1977) Cellular migration and replication in endothelial regeneration: A study using irradiated endothe-lial cultures. Lab Invest 36: 18PubMedGoogle Scholar
  70. Spaet TH, Stemerman MB, Veith FJ, Lejniek I (1975) Intimal injury and re-growth in the rabbit aorta: Medial smooth muscle cells as a source of neointima. Circ Res 36: 58PubMedGoogle Scholar
  71. Skutelsky E, Rudich Z, Dano D (1975) Surface charge properties of the lumi-nal front of blood vessel walls: an electron microscopical analysis. Thromb Res 7: 623PubMedCrossRefGoogle Scholar
  72. Srinivasan SR, Dola P, Radhakrishuamunthy B, Pargonkar PS, Berenson GS (1975) Lipoprotein-acid mucopolysaccharide complexes of human atherosclerotic lesion. Biochim Biophys Acta 388: 58PubMedGoogle Scholar
  73. Stehbens WE (19 74) Haemodynamic production of lipid deposition, intimai tears, mural dissection and thrombosis in the blood vessel wall. Proc R Soc Lond (Biol) 185: 357CrossRefGoogle Scholar
  74. Stemerman MB, Ros R (1972) Experimental arteriosclerosis. I. Fibrous plaque formation in primates, an electron microscope study. J Exp Med 136: 769PubMedCrossRefGoogle Scholar
  75. Stevens RL, Colombo M, Gonzales JJ, Hollander W, Schmi K (1976) The glycos-aminoglycans of the human artery and their changes in atherosclerosis. J Clin Invest 58: 470PubMedCrossRefGoogle Scholar
  76. Thorgeirsson G, Robertson AL, Jr (19 78) The vascular endothelium — patho-biologic significance. Amer J Pathol 93: 803Google Scholar
  77. Thorgeirsson G, Robertson AL, Jr (1978) Platelet factors and the human vascular wall: Variations in growth response between endothelial and medial smooth muscle cells. Atherosclerosis 30: 67PubMedCrossRefGoogle Scholar
  78. Vlodavsky I, Fielding PE, Fielding CJ, Gospodarowic D (1978) Role of contact inhibition in the regulation of receptor-mediated uptake of low density lipoprotein in cultured vascular endothelial cells. Proc Natl Acad Sci USA 75(1): 356PubMedCrossRefGoogle Scholar
  79. Wall RT, Harker LA, Quadracci LJ, Striker GE (1978) Factors influencing endothelial cell proliferation in vitro. J Cell Physiol 96: 203PubMedCrossRefGoogle Scholar
  80. Weber G, Fabbrini P, Res L (1974) Scanning and transmission electron microscopy observations on the surface lining of aortic intimai plaques in rabbits on a hypercholesterolic diet. Virchows Arch A Pathol Anat Histol 364: 325PubMedCrossRefGoogle Scholar
  81. Weksler BB, Ley CW, Jaffe EA (1978) Stimulation of endothelial cell prosta-cyclin production by thrombin, trypsin, and the ionophore A 23187. J Clin Invest 62: 923PubMedCrossRefGoogle Scholar
  82. Weksler BB, Marcus AM, Jaffe EA (1977) Synthesis of prostaglandin l2 (pros-tacyclin) by cultured human and bovine endothelial cells. Proc Natl Acad Sci USA 74: 3922PubMedCrossRefGoogle Scholar
  83. Wight TN, Ross R (19 75) Proteoglycan in primate arteries. I. Ultrastructural localization and distribution in the intima. J Cell Biol 67: 660CrossRefGoogle Scholar
  84. Wright HP (1970) Endothelial turnover. In: Koller F, Brinkhous KM, Biggs R, Rodman NF, Hinnom S (eds) Vascular factors and thrombosis. Schattauer Verlag, New YorkGoogle Scholar
  85. Zetter BR, Johnson LK, Shuman MA, Gospodarowic D (1978) The isolation of vascular endothelial cell lines with altered cell surface and platelet-binding properties. Cell 14: 501PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag New York Inc. 1980

Authors and Affiliations

  • Michael A. GimbroneJr

There are no affiliations available

Personalised recommendations