Endothelial Dysfunction and Atherosclerosis

  • Russell Ross


The concept of endothelial “injury,” or dysfunction, has been central to the “response to injury” hypothesis of atherosclerosis, which was formulated in 19731 and has been modified and retested for the past 16 years.2–4 This hypothesis proposes that many forms of functional alteration may occur in the endothelium, some of which may have morphologic manifestations, whereas others may induce no visible change. These changes may lead to a series of cellular interactions at focal sites within the artery wall. They involve white cells of the blood (T lymphocytes and monocyte/macrophages) and cells of the artery wall (endothelium and smooth muscle) in a series of complex interactions that lead to the development of fatty streaks, fibrofatty (or intermediate) lesions, and ultimately to fibrous plaques, which may become the advanced, complicated, ulcerated, or calcified occlusive lesions of atherosclerosis.


Smooth Muscle Cell Nonhuman Primate Artery Wall Fatty Streak Short Arrow 
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. 1.
    Ross, R., and Glomset, J., 1973, Atherosclerosis and the arterial smooth muscle cell, Science 180:1332–1339.PubMedCrossRefGoogle Scholar
  2. 2.
    Ross, R., and Glomset, J. A., 1976, The pathogenesis of atherosclerosis, N. Engl. J. Med. 295:369–377, 420–425.PubMedCrossRefGoogle Scholar
  3. 3.
    Ross, R., 1981, Atherosclerosis—A problem of the biology of arterial wall cells and their interaction with blood components, Arteriosclerosis 1:293–311.PubMedCrossRefGoogle Scholar
  4. 4.
    Ross, R., 1986, The pathogenesis of atherosclerosis—An update, N. Engl. J. Med. 314:488–500.PubMedCrossRefGoogle Scholar
  5. 5.
    Faggiotto, A., Ross, R., and Harker, L., 1984, Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation, Arteriosclerosis 4:323–340.PubMedCrossRefGoogle Scholar
  6. 6.
    Faggiotto, A., and Ross, R., 1984, Studies of hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque, Arteriosclerosis 4:341–356.PubMedCrossRefGoogle Scholar
  7. 7.
    Masuda, J., and Ross, R., 1990, Low-level hypercholesterolemia in the nonhuman primate. I. Fatty streak formation, Arteriosclerosis 10:164–177.PubMedCrossRefGoogle Scholar
  8. 8.
    Masuda, J., and Ross, R., 1990, Atherogenesis during low-level hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque, Arteriosclerosis 10:178–187.PubMedCrossRefGoogle Scholar
  9. 9.
    Vilcek, J., Gray, P. W., Rinderknecht, E., and Sevastopoulos, 1985, Interferon-7: A lymphokine for all seasons, Lymphokines 11:1–22.Google Scholar
  10. 10.
    Shimokado, K., Raines, E. W., Madtes, D. K., Barrett, T. B., Benditt, E. P., and Ross, R., 1985, A significant part of macrophage-derived growth factor consists of at least two forms of PDGF, Cell 43:277–286.PubMedCrossRefGoogle Scholar
  11. 11.
    Nathan, C. F., 1987, Secretory products of macrophages, J. Clin. Invest. 79:319–326.PubMedCrossRefGoogle Scholar
  12. 12.
    Dinarello, C. A., 1984, Interleukin-1, Rev. Infect. Dis. 6:51–95.PubMedCrossRefGoogle Scholar
  13. 13.
    Madtes, D. K., Raines, E. W., Sakariassen, K. S., Assoian, R. K., Sporn, M. B., Bell, G. I., and Ross, R., 1988, Induction of transforming growth factor-α in activated human alveolar macrophages, Cell 53:285–293.PubMedCrossRefGoogle Scholar
  14. 14.
    Assoian, R. K., Fleudelys, B. E., Stevenson, H. C., Miller, P. J., Madtes, D. K., Raines, E. W., Ross, R., and Sporn, M. B., 1987, Expression and secretion of type β transforming growth factor by activated human macrophages, Proc. Natl. Acad. Sci. USA 84:6020–6024.PubMedCrossRefGoogle Scholar
  15. 15.
    Ralph, P., 1989, Colony stimulating factors, in: Human Monocytes (M. Zembala and G. Asherson, eds.), Academic Press, New York, pp. 228–246.Google Scholar
  16. 16.
    Dinarello, C. A., 1988, Biology of interleukin 1, FASEB J. 2:108–115.PubMedGoogle Scholar
  17. 17.
    Antonelli-Orlidge, A., Saunders, K. B., Smith, S. R., and D’Amore, P. A., 1989, An activated form of transforming growth factor β is produced by cocultures of endothelial cells and pericytes, Proc. Natl. Acad. Sci. USA 86:4544–4548.PubMedCrossRefGoogle Scholar
  18. 18.
    Sato, Y., and Rifkin, D. B., 1989, Inhibition of endothelial cell movement of pericytes and smooth muscle cells: Activation of a latent transforming growth factor-β1-like molecule by plasmin during co-culture, J. Cell Biol. 109:309–315.PubMedCrossRefGoogle Scholar
  19. 19.
    Raines, E. W., Bowen-Pope, D. F., and Ross, R., 1990, Platelet-derived growth factor, in: Handbook of Experimental Pharmacology: Peptide Growth Factors and Their Receptors, Vol. 95/1 (M. B. Sporn and A. B. Roberts, eds.), Springer-Verlag, Berlin, pp. 173–262.Google Scholar
  20. 20.
    Ross, R., Raines, E. W., and Bowen-Pope, D. F., 1986, The biology of platelet-derived growth factor, Cell 46:155–169.PubMedCrossRefGoogle Scholar
  21. 21.
    Simionescu N., Vasile, E., Lupu, F., Popescu, G., and Simionescu, M., 1986, Prelesional events in atherogenesis. Accumulation of extracellular cholesterol-rich liposomes in the arterial intima and cardiac valves of the hyperlipidemic rabbit, Am. J. Pathol. 123:109–125.PubMedGoogle Scholar
  22. 22.
    Parthasarathy, S., Quinn, M. T., Schwenke, D. C., Carew, T. E., and Steinberg, D., 1989, Oxidative modification of beta-very low density lipoprotein. Potential role in monocyte recruitment and foam cell formation, Arteriosclerosis 9:398–404.PubMedCrossRefGoogle Scholar
  23. 23.
    Gerrity, R. G., 1981, The role of the monocyte in atherogenesis. I. Transition of blood-borne monocytes into foam cells in fatty lesions, Am. J. Pathol. 103:181–190.PubMedGoogle Scholar
  24. 24.
    Sporn, M. B., Roberts, A.B., Wakefield, L. M., and de Crombrugghe, B., 1987, Some recent advances in the chemistry and biology of transforming growth factor-beta, J. Cell Biol. 105:1039–1045.PubMedCrossRefGoogle Scholar
  25. 25.
    Heimark, R. L., Twardzik, D., and Schwartz, S. M., 1986, Inhibition of endothelial regeneration by type-beta transforming growth factor from platelets, Science 233:1078–1080.PubMedCrossRefGoogle Scholar
  26. 26.
    Ignotz, R. A., and Massague, J., 1986, Transforming growth factor-ß stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix, J. Biol. Chem. 261:4337–4345.PubMedGoogle Scholar
  27. 27.
    Leof, E. B., Proper, J. A., Goustin, A. S., Shipley, G. D., DiCorleto, P. E., and Moses, H. L., 1986, Induction of c-sis mRNA and activity similar to platelet-derived growth factor by transforming growth factor beta: A proposed model for indirect mitogenesis involving autocrine activity, Proc. Natl. Acad. Sci. USA 83:2453–2457.PubMedCrossRefGoogle Scholar
  28. 28.
    Miyazono, K., Okabe, T., Urabe, A., Takaku, F., and Heldin, C.-H., 1987, Purification and properties of an endothelial cell growth factor from human platelets, J. Biol. Chem. 262:4098–4103.PubMedGoogle Scholar
  29. 29.
    Ishikawa, F., Miyazono, K., Hellman, U., Drexler, H., Wernstedt, C., Hagiwara, K., Usuki, K., Fumimaro, T., Risau, W., and Heldin, C.-H., 1989, Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor, Nature 338:557–562.PubMedCrossRefGoogle Scholar
  30. 30.
    Baird, A., Mormede, P., and Bohlen, P., 1985, Immunoreactive fibroblast growth factor in cells of peritoneal exudate suggests its identity with macrophage-derived growth factor, Biochem. Biophys. Res. Commun. 126: 358–364.PubMedCrossRefGoogle Scholar
  31. 31.
    Hajjar, K. A., Hajjar, D. P., Silverstein, R. L., and Nachman, R. L., 1987, Ibmor necrosis factor-mediated release of platelet-derived growth factor from cultured endothelial cells, J. Exp. Med. 166:235–245.PubMedCrossRefGoogle Scholar
  32. 32.
    Raines, E. W., Dower, S. K., and Ross, R., 1989, IL-1 mitogenic activity for fibroblasts and smooth muscle cells is due to PDGF-AA, Science 243:393–396.PubMedCrossRefGoogle Scholar
  33. 33.
    DiCorleto, P. E., and Bowen-Pope, D. F., 1983, Cultured endothelial cells produce a platelet-derived growth factor-like protein, Proc. Natl. Acad. Sci. USA 80:1919–1923.CrossRefGoogle Scholar
  34. 34.
    Emeson, E. E., and Robertson, A. L., Jr., 1988, T lymphocytes in aortic and coronary intimas. Their potential role in atherogenesis, Am. J. Pathol. 130:369–376.PubMedGoogle Scholar
  35. 35.
    Hansson, G. K., Jonasson, L., Holm, J., and Claesson-Welsh, L., 1986, Class II MHC antigen expression in the atherosclerotic plaque: Smooth muscle cells express HLA-DR, HLA-DQ and the invariant gamma chain, Clin. Exp. Immunol. 64:261–268.PubMedGoogle Scholar
  36. 36.
    Jonasson, L., Holm, J., and Hansson, G. K., 1988, Smooth muscle cells express la antigens during arterial response to injury, Lab. Invest. 58:310–315.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Russell Ross
    • 1
  1. 1.Department of PathologyUniversity of WashingtonSeattleUSA

Personalised recommendations