The Central Nervous System and Atherogenesis: Interrelationships

  • William H. Gutstein
  • Joseph M. Wu
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 273)


Despite almost a century of scientific study since Anitschkov and Chalatov1 observed that cholesterol feeding produced arterial lesions in rabbits, the etiology and pathogenesis of atherosclerosis (AS) remain unknown. In humans, clinical complications and sequelae occur when the lesions have evolved to produce the fibrous plaque. The main histologic features of this stage are lipid accumulation and fibroelastic and fibromuscular thickening, which initially are present in a patchy distribution but later become more diffuse as individual plaques coalesce. A fatty streak stage, characterized by lipid accumulation within intimal cells, either of monocyte/ macrophage or arterial smooth muscle cell (ASMC) origin, to give them a “foam cell” appearance in histologic sections, is considered by some to represent an intermediate step in the development of the final lesion.2


Lipid Accumulation Squirrel Monkey Endothelial Injury Bile Duct Ligation Stimulation Mitogen 
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.
    N. N. Anitschkov, and S. Chalatov, Uber Experimentalle Cholesterinsteatose und Ihre Bedeutung fur die Entstehung Einiger Pathologischer Prozesse. Zbl. allg. Path. path. Anat. 24:1 (1913).Google Scholar
  2. 2.
    H. C. McGill, Jr., Fatty Streaks in the Coronary Arteries and Aorta. Lab. Invest. 18:560 (1968).PubMedGoogle Scholar
  3. 3.
    R. Ross, and J. Glomset, Medical Progress. The Pathogenesis of Atherosclerosis, New Eng. J. Med. 295:369 (1976).295:420 (1976).PubMedCrossRefGoogle Scholar
  4. 4.
    A. Keys, Coronary heart disease in seven countries. Circulation 41:I-1 (1970).Google Scholar
  5. 5.
    R. Doll, and R. Peto, Mortality in Relation to Smoking — 20 Years Observation in Male British Doctors, Br. Med. J. 2:1525 (1976).PubMedCrossRefGoogle Scholar
  6. 6.
    D. S. Bloom, B. H. Eidelman, and T. A. McCalden, Modification of the Cerebrovascular Response to Noradrenaline by Bile Duct Ligation, Gut 16:1723 (1975).CrossRefGoogle Scholar
  7. 7.
    R. S. Eliot, Coronary Artery Heart Disease: Biobehavioral Factors, Overview, in: Circulation, Suppl. (Part 2, Vol. 76,) J. T. Shepherd, and S. M. Weiss, eds. (1987).Google Scholar
  8. 8.
    R. B. Williams, Jr., Psychological Factors in Coronary Artery Disease: Epidemiologic Evidence, IBID., ref. 7, I-117.Google Scholar
  9. 9.
    C. D. Jenkins, J. Zyzanski, T. J. Ryan, A. Flessas, and S. I. Tannenbaum, Social Insecurity and Coronary-Prone Type A Responses as Identifiers of Severe Atherosclerosis, J. Consult. Clin. Phyiol. 45:1060 (1977).CrossRefGoogle Scholar
  10. 10.
    T. B. Clarkson, J. R. Kaplan, M. R. Adams, and S. B. Manuck, Phychosocial Influences on the Pathogenesis of Atherosclerosis Among Nonhuman Primates, IBID., ref. 7, I-29.Google Scholar
  11. 11.
    P. D. MacLean, The Hypothalamus and Emotional Behavior, in: “The Hypothalamus,” W. Haymaker, E. Anderson, and W. J. Nauta, eds., Charles C. Thomas, Springfield, Illinois (1969).Google Scholar
  12. 12.
    P. T. Costa, (Chairman), Task Force 2: Psychological Risk Factors in Coronary Artery Disease, IBID, ref. 7, I-145.Google Scholar
  13. 13.
    A. Maseri, and S. Chierchia, Coronary Artery Spasm: Demonstration, Definition, Diagnosis, and Consequences, Prog. Cardiovasc. Dis. 25:169 (1982).PubMedCrossRefGoogle Scholar
  14. 14.
    R. F. Rushmore, “Structure and Function of the Cardiovascular System,” Second Edit. W. B. Saunders Company, Phila. (1976).Google Scholar
  15. 15.
    W. H. Gutstein, P. Anversa, C. Beghi, G. Kiu, and D. Pacanovsky, Coronary Artery Spasm in the Rat Induced by Hypothalamic Stimulation, Atherosclerosis 51:135 (1984).PubMedCrossRefGoogle Scholar
  16. 16.
    W. H. Gutstein, P. Anversa, and G. Guideri, Spasm of Small Coronary Arteries and Ischemic Myocardial Injury Induced by Hypothalamic Stimulation, Am. J. Pathol. 129:287 (1987).PubMedGoogle Scholar
  17. 17.
    N. Weckman, Local Constriction and Spasm of Large Arteries Elicited by Hypothalamic Stimulation, Experientia 16:34 (1960).PubMedCrossRefGoogle Scholar
  18. 18.
    K. I. Melville, B. Blum, H. E. Shister, and M. D. Silver, Cardiac Ischemic Changes and Arrhythmias Induced by Hypothalamic Stimulation, Amer. J. Cardiol. 12:781 (1963).PubMedCrossRefGoogle Scholar
  19. 19.
    C. C. Chi, and J. P. Flynn, The Effects of Hypothalamic and Reticular Stimulation on Evoked Responses in the Visual System of the Cat, Electroenceph. Clin. Neurophysiol. 24:343 (1968).PubMedCrossRefGoogle Scholar
  20. 20.
    H. L. Garvey, and I. I. Melville, Cardiovascular Effects of Lateral Hypothalamic Stimulation in Normal and Coronary-Ligated Dogs, J. Cardiovasc. Surg. 10:377 (1969).Google Scholar
  21. 21.
    H. L. Garvey, and E. I. Melville, Effects of Verapamil on Cardiovascular Responses to Lateral Hypothalamic Stimulation in Normal and Coronary-Ligated Dogs, Canad. J. Physiol. Pharmacol. 47:675 (1969).CrossRefGoogle Scholar
  22. 22.
    M. H. Evans, An Effect of Hypothalamic Stimulation On Cardiac Output in the Rabbit, Quart. J. Exp. Physiol. 65:217 (1980).PubMedGoogle Scholar
  23. 23.
    M. H. Evans, Vasoactive Sites in the Diencephalon of the Rabbit, Brain Res. 183:329 (1980).PubMedCrossRefGoogle Scholar
  24. 24.
    B. Blum, J. Israeli, M. Dujovny, A. Davidovich, and M. Farchi, Angina-Like Cardiac Disturbances of Hypothalamic Etiology in Cat, Monkey, and Man, Israel J. Med. Sci. 18:127 (1982).PubMedGoogle Scholar
  25. 25.
    A. C. Bonham, D. D. Gutterman, J. M. Arthur, M. L. Marcus, G. F. Gebhart, and M. J. Brody, Electrical Stimulation in Perifornical Lateral Hypothalmus Decreases Coronary Blood Flow in Cats. Am. J. Physiol. 252:H474 (1987).PubMedGoogle Scholar
  26. 26.
    W. H. Gutstein, J. N. LaTaillade, and L. Lewis, Role of Vasoconstriction In Experimental Arteriosclerosis, Circ. Res. 10:925 (1962).PubMedGoogle Scholar
  27. 27.
    C. J. Schwartz, J. L. Kelley, R. M. Nerem, E. A. Sprague, M. M. Rozek, A. J. Valente, E. H. Edwards, A. R. S. Prasad, J. J. Kerbacher, and S. A. Logan, Pathophysiology of the Atherogenic Process, Amer. J. Cardiol. 64:23G (1989).PubMedCrossRefGoogle Scholar
  28. 28.
    S. M. Schwartz, G. R. Campbell, and J. H. Campbell, Replication of Smooth Muscle Cells in Vascular Disease, Circ. Res. 58:427 (1986).PubMedGoogle Scholar
  29. 29.
    W. H. Gutstein, A. R. D’Aguillo, F. Parl, and G. Kiu, Influence of Hypothalamic Stimulation on Large Endothelial Space Formation in the Coronary Artery of the Rat, Artery 1:385 (1975).Google Scholar
  30. 30.
    W. H. Gutstein, J. Harrison, F. Parl, G. Kiu, and M. Avitable, Nerual Factors Contribute to Atherogenesis, Science 199:449 (1978).PubMedCrossRefGoogle Scholar
  31. 31.
    W. H. Gutstein, P. Anversa, G. K. Turi, L. Korcek, J. E. Harrison, and G. Kiu, Effect of Hypothalamic Stimulation on the Endothelial Morphology of the Aorta in the Conscious Squirrel Monkey, Atherosclerosis. 39:329 (1981).PubMedCrossRefGoogle Scholar
  32. 32.
    W. H. Gutstein, C-H. Wang, L. Korcek, J. E. Harrison, and D. Pacanovsky, Proliferation of Arterial Smooth Muscle Cells Incubated in Serum From Brain-Stimulated Rats, Life Sci. 34:2627 (1984).PubMedCrossRefGoogle Scholar
  33. 33.
    W. H. Gutstein, J. M. Wu, Unpublished Observations.Google Scholar
  34. 34.
    W. H. Gutstein, D. J. Schneck, and H. Appleton, Association of Increased Plasma Lipid Levels with Brain Stimulation, Metabolism 17:535 (1968).PubMedCrossRefGoogle Scholar
  35. 35.
    W. H. Gutstein, and G. A. Farrell, Serum Cholesterol Responses to Hypothalamic Stimulation and Fatty Acid Administration in the Rat, Proc. Soc. Exp. Biol. Med. 141:137 (1972).PubMedGoogle Scholar
  36. 36.
    W. H. Gutstein, D. J. Schneck, and H. Appleton, Mechanism of Plasma Lipid Increases Following Brain Stimulation, Metabolism 17:535 (1968).PubMedCrossRefGoogle Scholar
  37. 37.
    N. Blaes, and J. P. Boissel, Growth Stimulating Effects of Catecholamines on rat Aortic Smooth Muscle Cells in Culture. J. Cell Physiol. 116:167 (1983).PubMedCrossRefGoogle Scholar
  38. 38.
    M. Campbell-Boswell, and A. Lazzarini-Robertson, Jr. Effects of Angiotensin II and Vasopressin on Human Smooth Muscle Cells in Vitro, Exper. Molec. Pathol. 35:265 (1981).CrossRefGoogle Scholar
  39. 39.
    R. F. Furchgott, and J. V. Zawadzki, The Obligatory Role of Endothelial Cells in the Relaxation of Arterial Smooth Muscle by Acetylcholine, Nature 288:373 (1980).PubMedCrossRefGoogle Scholar
  40. 40.
    M. Yanagisawa, H. Kurihara, S. Kimura, Y. Tomobe, M. Kobayashi, Y. Mitsui, Y. Yazaki, K. Gote and T. Masaki, A Novel Potent Vasoconstrictor Peptide Produced by Vascular Endothelial Cells, Nature 332:411 (1988).PubMedCrossRefGoogle Scholar
  41. 41.
    J. R. Patsch, K. C. Aune, A. M. Gotto, Jr. and J. D. Morrisett, Isolation, Chemical Characterization, and Biophysical Properties of Three Different Abnormal Lipoproteins: J. Bio. Chem. 252:2113 (1977).Google Scholar
  42. 42.
    F. Parl, L. D. Bjornson, G. Kiu, and W. H. Gutstein, Effects of Electrical Brain Stimulation on Erythrocyte Membrane Lipids, Life Sci. 20:1983 (1977).PubMedCrossRefGoogle Scholar
  43. 43.
    F. M. Abboud, and M. D. Thames, Interaction of Cardiovascular Reflexes in Circulatory Control, in: “Handbook of Physiology, Section 2: Circulation III, Peripheral Circulation and Organ Blood Flow, Part 2,” Amer. Physiol. Soc, Bethesda (1983).Google Scholar
  44. 44.
    B. L. Languille, M. Reidy, and R. L. Kline, Injury and Repair of Endothelium at Sites of Flow Disturbances Near Abdominal Aortic Coarctations in Rabbits, Atherosclerosis. 6:146 (1986).Google Scholar
  45. 45.
    P. Constantinides, and M. Robinson, Ultrastructural Injury of Arterial Endothelium, II. Effect of Vasoactive Amines, Arch Pathol. 88:106 (1969).PubMedGoogle Scholar
  46. 46.
    I. Joris, and G. Majno, Endothelial Changes Induced by Arterial Spasm, Am. J. Pathol. 102:346 (1981).PubMedGoogle Scholar
  47. 47.
    S. D. Gertz, M. S. Forbes, S. Tunaga, J. Kawamura, M. L. Renneis, T. Shimamoto, and E. Nelson, Ischemic Carotid Endothelium, Transmission Electron Microscopic Studies, Arch. Pathol. Lab. Med. 100:346 (1976).Google Scholar
  48. 48.
    I. Joris, and G. Majno, Medial Changes in Arterial Spasm Induced by L-Norepinephrine, Am. J. Pathol. 105:212 (1981).PubMedGoogle Scholar
  49. 49.
    J. E. Dimsdale, and J. A. Herd, Variability of Plasma Lipids in Response to Emotional Arousal, Psychosom. Med. 44:413 (1982).PubMedGoogle Scholar
  50. 50.
    N. Schneiderman, Psychophysiologic Factors in Atherogenesis and Coronary Artery Disease, IBID., ref 7, I-41.Google Scholar
  51. 51.
    W. H. Gutstein, D. J. Schneck, F. A. Farrell, and W. Long, Jr. Hypothalamically Induced Hyperlipidemia, Protection by Pentaerythritol Tetranitrate, Metabolism 19:230 (1970).PubMedCrossRefGoogle Scholar
  52. 52.
    D. Seidel, P. Alaupovic, and R. H. Furman, A Lipoprotein Characterizing Obstructive Jaundice, I. Method for Quantitative Separation and Identification of Lipoproteins in Jaundiced Subjects, J. Clin. Invest. 48:1211 (1969).PubMedCrossRefGoogle Scholar
  53. 53.
    D. Seidel, P. Alaupovic, R. H. Furman, and W. J. McConathy, A Lipoprotein Characterizing Obstructive Jaundice, II. Isolation and Partial Characterization of the Protein Moieties of Low Density Lipoproteins, J. Clin. Invest. 49:2396 (1970).PubMedCrossRefGoogle Scholar
  54. 54.
    D. Seidel, B. Agostini, and P. Muller, Structure of an Abnormal Plasma Lipoprotein (LP-X) Characterizing Obstructive Jaundice, Biochem. Biophys. Acta 260:146 (1972).PubMedGoogle Scholar
  55. 55.
    G. R. Campbell, and J. H. Chamley-Campbell, Invited Review, The Cellular Pathobiology of Atherosclerosis, Pathol. 13:423 (1981).CrossRefGoogle Scholar
  56. 56.
    J. C. Geer, and M. D. Haust, “Monographs on Atherosclerosis, Vol. 2, Smooth Muscle Cells in Athersoclerosis, S. Karger, Basel (1972).Google Scholar
  57. 57.
    A. W. Clowes, and M. J. Karnovsky, Suppression by Heparin of Smooth Muscle Cell Proliferation in Injured Arteries, Nature (London) 265:625 (1977).CrossRefGoogle Scholar
  58. 58.
    J. L. Goldstein, and M. S. Brown, The Low Density Lipoprotein Pathoway and its Relation to Atherosclerosis, Annu. Rev. Biochem. 46:897 (1977).PubMedCrossRefGoogle Scholar
  59. 59.
    M. S. Brown, J. R. Faust, and J. L. Goldstein, Role of the Low Density Lipoprotein Receptor in Regulating the Content of Free and Esterified Cholesterol in Human Fibroblasts, J. Clin. Invest. 55:783 (1975).PubMedCrossRefGoogle Scholar
  60. 60.
    J. L. Goldstein, R. G. W. Anderson, L. M. Buja, S. K. Basu, and M. S. Brown, Overloading Human Aortic Smooth Muscle Cells with Low Density Lipoprotein-Cholesteryl Esters Reproduces Features of Atherosclerosis in Vitro, J. Clin. Invest. 59:1196 (1977).PubMedCrossRefGoogle Scholar
  61. 61.
    E. Gaither, Gallbladder Dis. Chap. XIV in: “Diseases of the Digestive System,” ed. S. A. Portis, Lea and Febiger, Phila. (1944).Google Scholar
  62. 62.
    S. A. Portisi, Jaundice, Chap. XVIII, IBID., ref. 61.Google Scholar
  63. 63.
    J. Webster, The Dutchess of Malfi, in: “Critical Temper”, Great Britain (1623).Google Scholar
  64. 64.
    G. Schettler, Factors that Modify, Aggravate and Prevent the Atheromatous Process, in: “Advances in Experimental Medicine and Biology, Vol. 16B, The Artery and the Process of Arteriosclerosis,” S. Wolf, ed., Plenum Press, New York (1972).Google Scholar
  65. 65.
    A. K. Diehl, S. M. Haffner, H. P. Hazuda, and M. P. Stern, Coronary Risk Factors and Clinical Gallbladder Disease: An Approach to the Prevention of Gallstones? Amer. J. Publ. Health 77:841 (1987).CrossRefGoogle Scholar
  66. 66.
    G. Weissmann, D. Bloomgarden, R. Kaplan, C. Cohen, S. Hoffstein, T. Collins, A. Gotlieb, and D. Nagle, A General Method for the Introduction of Enzymes, by Means of Immunoglobulin-Coated Liposomes, into Lysosomes of Deficient Cells, Proc. Nat. Acad. Sci. USA, 72:88 (1975).PubMedCrossRefGoogle Scholar
  67. 67.
    D. Papahadjopoulous, E. Mayhew, G. Poste, and S. Smith, Incorporation of Lipid Vesicles by Mammalian Cells Provide a Potential Method for Modifying Cell Behavior, Nature 252:163 (1974).CrossRefGoogle Scholar
  68. 68.
    N. Simionescu, E. Vasile, F. Lupu, G. Popescu, and M. Simionescu, 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 (1986).PubMedGoogle Scholar
  69. 69.
    R. Mora, F. Lupu, and N. Simionescu, Prelesional Events in Atherogenesis, Colocalization of Apolipoprotein B, Unesterified Cholesterol and Extracellular Phospholipid Liposomes in the Aorta of Hyperlipidemic rabbit, Atherosclerosis 67:143 (1987).PubMedCrossRefGoogle Scholar
  70. 70.
    H. S. Kruth, Filipin-Positive, Oil Red O-Negative Particles in the Atherosclerotic Lesions Induced by Cholesterol Feeding, Lab. Inves. 50:87 (1983).Google Scholar
  71. 71.
    H. S. Kruth, Localization of Unesterified Cholesterol in Human Atherosclerotic Lesions, Demonstration of Filipin-Positive, Oil-Red-O- Negative Particles, Amer. J. Pathol. 114:201 (1983).Google Scholar
  72. 72.
    G. Kober, W. Schneider, and M. Kaltenbach, Can the Progression of Coronary Sclerosis be Influenced by Calcium Antagonists? J. Cardio. Pharm. 13:S2.Google Scholar
  73. 73.
    S.A. Hilton, Hypothalamic Regulation of the Cardiovascular System, Br. Med. Bull. 22:243 (1966).PubMedGoogle Scholar
  74. 74.
    W. R. Hess, and M. Brugger, Das Subkortikale Zentrum der Affektiven Abwehrreaktion, Helv. Physiol. Acta 1:33 (1943).Google Scholar
  75. 75.
    C. W. Sem-Jacobsen, Effects of Electrical Stimulation on the Human Brain, Electroenceph. Clin. Neurophysiol. 11:379 (1959).Google Scholar
  76. 76.
    R. G. Heath, and W. A, Mickle, Evaluation of Seven Years Experience with Depth Electrode Studies inHuman Patients, in: “Electrical Studies on the Unanesthetized Brain,” E. R. Ramey, and D. S. O. Doherty, eds., Paul B. Hoeber, New York (1960).Google Scholar
  77. 77.
    C. W. Sem-Jacobsen, and A. Torkildsen, Depth Recording and Electrical Stimulation in the Human Brain, Ibid, ref. 76, p. 275.Google Scholar
  78. 78.
    R. G. Heath, Pleasure Response of Human Subjects to Direct Stimulation of the Brain, Physiologic and Psychodynamic Consideration, in: “The Role of Pleasure in Behavior,” R. G. Heath, ed., Harper and Row, New York (1964).Google Scholar
  79. 79.
    S. M. Schwartz, C. C. Haudenschid, E. M. Eddy, Endothelial Regeneration I. Quantitative Analysis of Initial Stages of Endothelial Regeneration in Rat Aortic intima, Lab. Invest. 38:568 (1978).PubMedGoogle Scholar
  80. 80.
    C. C. Haudenschild, and S. M. Schwartz, Endothelial Regeneration, II. Restitution of Endothelial Continuity, Lab. Invest. 41:407 (1979).PubMedGoogle Scholar
  81. 81.
    E. H. Ahrens, Jr., The Lipid Disturbance in Biliary Obstruction and its Relationship to the Genesis of Arteriosclerosis. Bull. N.Y. Acad. Med. :151 (1950).Google Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • William H. Gutstein
    • 1
  • Joseph M. Wu
    • 2
  1. 1.Department of PathologyNew York Medical CollegeValhallaUSA
  2. 2.Department of BiochemistryNew York Medical CollegeValhallaUSA

Personalised recommendations