Advertisement

Recruitment and dynamics of leukocytes in the formation of arterial intimal thickening — A comparative study with normo- and hypercholesterolemic rabbits

      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Leukocyte involvement in intimal thickening was investigated as a function of time and diet. Fibromuscular or foam cell-rich thickings were induced by electrical stimulation (ES) of carotid arteries in rabbits either on a normal or a high (1%) cholesterol diet. Under both dietary conditions granulocytes (predominantly neutrophils), monocytes and lymphocytes migrated through and accumulated beneath a continuous, yet structurally altered endothelium already after 1 day of ES. This preceded the occurrence of smooth muscle cells (SMCs) in the intima. Under normocholesterolemia, leukocyte attachment to the endothelium decreased with continued ES, which coincided with the re-establishment of a normal endothelial cell pattern Neutrophils ceased to invade the stimulated intima and disappeared from the lesion after 14 days. The proportion of mononuclear leukocytes was also reduced in the thickened intima, finally amounting to 5.5 ± 5.9% in the 4-week-old fibromuscular lesion where SMCs prevailed. Hypercholesterolemia did not affect neutrophil involvement in response to ES. However, it provoked lipid deposition first in macrophages, then in SMCs and resulted in elevated amounts of mononuclear leukocytes both within the foam cell-rich thickening and in association with the overlying endothelium. These data indicate adaptive behavior of leukocytic infiltration in the development of fibromuscular thickening, and a shift to a chronic inflammatory response under additional hypercholesterolemia.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Klurfeld D.M.
        Interactions of immune function with lipids and atherosclerosis.
        CRC Crit. Rev. Toxicol. 1983; 11: 333
        • Munro J.M.
        • Cotran R.S.
        The pathogenesis of atherosclerosis: atherogenesis and inflammation.
        Lab. Invest. 1988; 58: 249
        • Watanabe T.
        • Tokunaga O.
        • Fan J.
        • Shimokama T.
        Atherosclerosis and macrophages.
        Acta. Pathol. Jpn. 1989; 39: 473
        • Stary H.C.
        • Blankenhorn D.H.
        • Chandler A.B.
        • Glagov S.
        • Instill W.
        • Richardson M.
        • Rosenfeld M.E.
        • Schaffer S.A.
        • Schwartz C.J.
        • Wagner W.D.
        • Wissler R.W.
        A definition of the intima of human arteries and of its atherosclerosis-prone regions.
        Arteriosclerosis Thromb. 1992; 12: 120
        • Hansson G.K.
        • Jonasson L.
        • Seifert P.S.
        • Stemme S.
        Immune mechanisms in atherosclerosis.
        Arteriosclerosis. 1989; 9: 567
        • Ross R.
        • Masuda J.
        • Raines E.W.
        • Gown A.M.
        • Katsuda S.
        • Sasahara M.
        • Malden L.T.
        • Masuko H.
        • Sato H.
        Localization of PDGF-B protein in macrophages in all phases of atherogenesis.
        Science. 1990; 248: 1009
        • Trillo A.A.
        The cell population of aortic fatty streaks in African green monkey with special reference to granulocytic cells. An ultrastructural study.
        Atherosclerosis. 1982; 43: 253
        • Stary H.C.
        • Malinow M.R.
        Ultrastructure of experimental coronary artery atherosclerosis in Cynomolgus Macaques.
        Atherosclerosis. 1982; 43: 151
        • Faggiotto A.
        • Ross R.
        Studies of hypercholesterolemia in the nonhuman primate. II. Fatty streak conversion to fibrous plaque.
        Arteriosclerosis. 1984; 4: 341
        • Prescott M.F.
        • Karboski McBride C.
        • Court M.
        Development of intimal lesions after leukocyte migration into the vascular wall.
        Am. J. Pathol. 1989; 135: 835
        • Cole C.W.
        • Makhoul R.G.
        • McCann R.L.
        • O'Malley M.K.
        • Hagen P.O.
        Vascular smooth muscle cells proliferate in vitro in response to human polymorphonuclear leukocytes and indomethacin.
        Clin. Invest. Med. 1985; 8: 228
        • Gerrity R.G.
        The role of the monocyte in atherogenesis. I. Transition of blood-borne monocytes into foam cells in fatty lesion.
        Am. J. Pathol. 1981; 103: 181
        • Joris J.
        • Zand T.
        • Nunnari J.J.
        • Krolikowski F.J.
        • Majno G.
        Studies on the pathogenesis of atherosclerosis. 1. Adhesion and emigration of mononuclear cells in the aorta of hypercholesterolemic rats.
        Am. J. Pathol. 1983; 113: 341
        • Faggiotto A.
        • Ross R.
        • Harker E.
        Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation.
        Arteriosclerosis. 1984; 4: 323
        • Schwartz C.J.
        • Sprague E.A.
        • Kelly J.L.
        • Valente A.J.
        • Suenram C.A.
        Aortic intimal monocyte recruitment in the normo and hypercholesterolemic baboon (Papio cynocephalus). An ultrastructural study: Implications in atherogenesis.
        Virchows Arch. [Pathol. Anat.]. 1985; 405: 175
        • Hansson G.K.
        • Seifert P.S.
        • Olsson G.
        • Bondjers G.
        Immunohistochemical detection of macrophages and T lymphocytes in atherosclerotic lesions of cholesterol-fed rabbits.
        Arteriosclerosis Thromb. 1991; 11: 745
        • Haudenschild C.
        • Studer A.
        Early interactions between blood cells and severely damaged rabbit aorta.
        Eur. J. Clin. Invest. 1971; 2: 1
        • Huth F.
        • Kojimahara M.
        • Franken T.
        • Rhedin P.
        • Rosenbauer K.A.
        Aortic alterations in rabbits following sheathing with silastic and polyethylene tubes.
        Curr. Top. Pathol. 1975; 60: 1
        • Hirosumi J.
        • Nomoto A.
        • Ohkubo Y.
        • Sekiguchi C.
        • Mutoh S.
        • Yamaguchi I.
        • Aoki H.
        Inflammatory - responses in cuff-induced atherosclerosis in rabbits.
        Atherosclerosis. 1987; 64: 243
        • Clowes A.W.
        • Clowes M.M.
        • Au Y.P.T.
        • Reidy M.A.
        • Belin D.
        Smooth muscle cells express urokinase during mitogenesis and tissue-type plasminogen activator during migration in injured rat carotid artery.
        Circ. Res. 1990; 67: 61
        • Clowes A.W.
        • Ryan G.B.
        • Breslow J.L.
        • Karnovsky M.J.
        Absence of enhanced endothelial thickening in the response of the carotid arterial wall to endothelial injury in hypercholesterolemic rats.
        Lab. Invest. 1976; 35: 6
        • Betz E.
        • Schlote W.
        Responses of vessel walls to chronically applied electrical stimuli.
        Basic. Res. Cardiol. 1979; 74: 10
        • Kling D.
        • Holzschuh T.
        • Betz E.
        Temporal sequence of morphological alterations in artery walls during experimental atherogenesis - occurrence of leukocytes.
        Res. Exp. Med. 1987; 187: 237
        • Heinle H.
        Metabolite concentration gradients in the arterial wall of experimental atherosclerosis.
        Exp. Med. Pathol. 1987; 46: 312
        • Zand T.
        • Underwood J.M.
        • Nunnar J.J.
        • Majno G.
        • Joris I.
        Endothelium and “silver lines”.
        Virchows Arch. [Pathol. Anat.]. 1982; 395: 133
        • Kling D.
        • Fingerle J.
        • Harlan J.M.
        Inhibition of leukocyte extravasation with a monoclonal antibody to CD18 during formation of experimental intimal thicken ing in rabbit carotid arteries.
        Arteriosclerosis Thromb. 1992; 12: 997
        • Holm S.
        A simple sequentially rejective multiple test procedure.
        Scand. J. Stat. 1979; 6: 65
        • Betz E.
        • Strohschneider T.
        The time course in the development of experimentally induced atheromas.
        in: 8th edn. Atherosclerosis VIII. Excerpta Medica, Amsterdam, York, Oxford1989: 141-144
        • Simionescu N.
        • Vasile E.
        • Lupu F.
        • Popescu G.
        • Simionescu M.
        Prelesional events in atherogenesis. Accumulation of extracellular cholesterol-rich liposomes in the arterial intima and cardiac valves of the hyperlipidemic rabbit.
        Am. J. Pathol. 1986; 123: 109
        • Kruth H.S.
        Subendothelial accumulation of unesterified cholesterol. An early event in atherosclerotic lesion development.
        Atherosclerosis. 1985; 57: 337
        • Booth R.F.G.
        • Martin J.F.
        • Honey A.C.
        • Hassall D.G.
        • Beesley J.E.
        • Moncada S.
        Rapid development of atherosclerotic lesions in the rabbit carotid artery induced by perivascular manipulation.
        Atherosclerosis. 1989; 76: 257
        • Betz E.
        • Fallier-Becker P.
        • Wolburg-Buchholz K.
        • Fotev Z.
        Proliferation of smooth muscle cells in the inner and outer layers of the tunica media of arteries: An in vitro study.
        J. Cell. Physiol. 1991; 147: 385
        • Kling D.
        • Holzschuh T.
        • Strohschneider T.
        • Betz E.
        Enhanced endothelial permeability and invasion of leukocytes into the artery wall as initial events in experimental arteriosclerosis.
        Inter. Angio. 1987; 6: 21
        • Reidy M.
        • Schwartz S.
        Endothelial regeneration: III. Time course of intimal changes after small defined injury to rat aortic endothelium.
        Lab. Invest. 1981; 44: 301
        • Wallis W.J.
        • Harlan J.M.
        Effector functions of endothelium in inflammatory and immunologic reactions.
        Pathol. Immunopathol. Res. 1986; 5: 73
        • Springer T.A.
        Adhesion receptors of the immune system.
        Nature 346. 1990; : 425
        • Butcher E.C.
        Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversity.
        Cell. 1991; 67: 1033
        • Robinson K.R.
        The responses of cells to electrical fields. A review.
        J. Cell. Biol. 1985; 101: 2023
        • Born G.V.R.
        • Planker M.
        Toward the mechanisms of the intravascular adhesion of granulocytes in inflamed vessels.
        in: 8th edn. Advances in In flammation Research. Vol. 1. Raven Press, New York1979: 117-137
        • Colditz I.G.
        • Movat H.Z.
        Chemotactic factorspecific desensitization of skin to infiltration by polymorphonuclear leukocytes.
        Immunol. Lett. 1984; 8: 83
        • Cybulsky M.I.
        • Gimbrone M.A.
        Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis.
        Science. 1991; 261: 788
        • Polacek D.
        • Byrne R.E.
        • Scanu A.M.
        Modification of low density lipoproteins by polymorphonuclear cell elastase leads to enhanced uptake by human monocytederived macrophages via the low density lipoprotein receptor pathway.
        J. Lipid Res. 1988; 29: 797
        • Gerrity R.G.
        The role of the monocyte in atherogenesis. II. Migration of foam cells from atherosclerotic lesions.
        Am. J. Pathol. 1981; 103: 191
        • Yui S.
        • Yamazaki M.
        Neutral lipid accumulation in macrophages during lipid-induced macrophage growth.
        J. Leukoc. Biol. 1989; 45: 189
        • Steinberg D.
        • Parthasarathy S.
        • Carew T.E.
        • Witztum J.L.
        Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity.
        N. Engl. J. Med. 1989; 320: 915
        • Wolfbauer G.
        • Glick J.M.
        • Minor L.K.
        • Rothblat G.H.
        Development of smooth muscle foam cell: Uptake of macrophage lipid inclusions.
        in: 8th edn. Proc. Nad. Acad. Sci. USA. 83. 1986: 7760
        • Shimokado K.
        • Raines E.W.
        • Madtes D.K.
        • Barrett T.B.
        • Benditt E.P.
        • Ross R.
        A significant part of macrophage-derived growth factor consists of at least two forms of PDGF.
        Cell. 1985; 43: 277
        • Martinet Y.
        • Bitterman P.B.
        • Mornex J.F.
        • Grotendorst G.R.
        • Martin G.R.
        • Crystal R.G.
        Activated human monocytes express the c-sis proto-oncogene and release a mediator showing PDGF-like activity.
        Nature. 1986; 319: 158
        • Ferns G.A.A.
        • Raines E.W.
        • Sprugel K.H.
        • Motani A.S.
        • Reidy M.A.
        • Ross R.
        Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF.
        Science. 1991; 253: 1129
        • Jawien A.
        • Bowen-Pope D.F.
        • Lindner V.
        • Schwartz S.M.
        • Clowes A.W.
        Platelet-derived growth factor promotes smooth muscle migration and intimal thicken ing in a rat model of balloon angioplasty.
        J. Clin. Invest. 1992; 89: 507
        • DiCorleto P.E.
        • Chisolm G.M.
        Participation of the endothelium in the development of the atherosclerotic plaque.
        Prog. Lipid Res. 1986; 25: 365
        • Zerwes H.G.
        • Risau W.
        Polarized secretion of a platelet-derived growth factor-like chemotactic factor by endothelial cells in vitro.
        J. Cell. Biol. 1987; 105: 2037
        • Lindner V.
        • Reidy M.A.
        Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor.
        in: 8th edn. Proc. Natl. Acad. Sci. USA. 88. 1991: 3739