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DOI: 10.1055/s-0037-1616233
Atherosclerosis and Thrombosis: Lessons from Animal Models
Publication History
Publication Date:
12 December 2017 (online)
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Summary
Atherothrombosis defines the occurrence of thrombosis on athero-sclerotic lesions. Atherosclerosis is the most prevalent disease of our time and its thrombotic complications are responsible for an exceedingly high number of deaths and disabilities. Over the past few years, experimental investigation and clinical and pathologic observations have led to a better understanding of how a thrombus forms and also of its incidence in acute ischemic syndromes. A thrombus is usually found secondary to atherosclerotic plaque disruption. Mural thrombosis, also at the site of plaque rupture, is an important mechanism in the progression of atherosclerosis even when symptoms are absent. Because atherosclerosis is a silent and asymptomatic disease until complications arise with thrombosis producing clinical symptoms, it is necessary to have models that reproduce the human disease in its early stages. Unfortunately, not all the experimental models of vascular disease have human resemblance and validity. Knowledge of the disease process and of what an experimental animal model can offer is a milestone for a successful investigation. Experimental models of vascular disease have enhanced our understanding of the pathophysiological processes leading to vascular obstruction in both spontaneous and accelerated atherosclerosis and thrombosis. Animal models have provided insight into the role of platelets, lipids, renin-angiotensin system (RAS), cytokines and growth factors in the evolution and progression of atherosclerosis and have suggested potential therapeutic interventions. Significant advances in our understanding of the vascular biology and pathology of atherosclerosis and thrombosis, and of the interactions of blood cells, lipids and proteins with the vascular wall, have allowed us to formulate new experimental hypotheses and to test therapeutic strategies, either pharmacological or surgical.
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References
- 1 Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAMA 1912; 59: 2015-20.
- 2 Benson RL. The present status of coronary arterial disease. Arch Pathol 1926; 2: 876-916.
- 3 Constantinides P. Plaque fissures in human coronary thrombosis. J Atheroscler Res 1966; 6I: 1-17.
- 4 DeWood 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.
- 5 DeWood MA, Stifter WF, Simpson CA. et al. Coronary arteriographic findings soon after non-Q wave myocardial infarction. N Engl J Med 1986; 315: 417-23.
- 6 Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983; 50: 127-34.
- 7 Falk E. Morphologic features of unstable atherothrombotic plaques underlying acute coronary syndromes. Am J Cardiol 1989; 63: 1114E-20E.
- 8 Falk E. Unstable angina with fatal outcome, dynamic coronary thrombosis leading to infarction and/or sudden death: autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 1985; 71: 699-708.
- 9 Richardson PD, Davies MJ, Born GVR. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaques. Lancet 1989; 2: 941-4.
- 10 Davies MJ, Bland MJ, Hartgartner WR. et al. Factors influencing the presence or absence of acute coronary thrombi in sudden ischemic death. Eur Heart J 1989; 10: 203-8.
- 11 Davies MJ. A macro and micro view of coronary vascular insult in ischemic heart disease. Circulation 1990; 82 (suppl II): 38-46.
- 12 Davies MJ, Thomas AC. Plaque fissuring-The cause of acute myocardial infarction, sudden ischemic death and crescendo angina. Br Heart J 1985; 53: 363-73.
- 13 Vogt MT, Wolfson SK, Kuller LH. Lower extremity arterial disease and the aging process: A review. J Clin Epidemiol 1992; 45: 529-42.
- 14 Cronenwett JL, Warner KG, Zelenock GB. et al. Intermittent claudication. Current results of non-operative management. Arch Surg 1984; 119: 430-6.
- 15 Farkouh ME, Rihal CS, Gersh BJ. et al. Influence of coronary heart disease on morbidity and mortality after lower extremity revascularization surgery: A population-based study in Olmsted County, Minnesota (1970-1987). J Am Coll Cardiol 1994; 24: 1290-6.
- 16 Dormandy J, Mahir M, Ascady G. et al. Fate of the patients with chronic leg ischemia. J Cardiovasc Surg 1989; 30: 50-7.
- 17 Davies MJ, Richardson PD, Woolf NW. et al. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J 1993; 69: 377-81.
- 18 Davila-Roman VG, Barzilai B, Wareing TH. et al. Atherosclerosis of the ascending aorta. Prevalence and role as an independent predictor of cerebrovascular events in cardiac patients. Stroke 1994; 25: 2012-6.
- 19 Jones EF, Kalman JM, Calafiore P. et al. Proximal aortic atheroma. An independent risk factor for cerebral ischemia. Stroke 1995; 26: 218-24.
- 20 Blauth CI, Cosgrove DM, Webb BW. et al. Atheroembolism from the ascending aorta. J Thorac Cardiovasc Surg 1992; 103: 1106-12.
- 21 Amarenco P, Cohen A, Tzourio C. et al. Atherosclerotic disease of the aortic arch and the risk factor of ischemic stroke. N Engl J Med 1994; 331: 1474-9.
- 22 The French Study of Aortic Plaques in Stroke Group.. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. N Engl J Med 1996; 334: 1216-21.
- 23 Fuster V, Ip JH, Badimon L. et al. Importance of experimental models for the development of clinical trials on thromboatherosclerosis. Circulation. 1991 83: IV-15-25.
- 24 Johnson GJ, Griggs TR, Badimon L. The utility of animal models in the preclinical study of interventions to prevent human coronary artery restenosis: analysis and recommendations. Thromb Haemostas 1999; 81: 835-43.
- 25 Fuster V, Falk E, Fallon J. et al. The three processes leading to post PTCA restenosis: Dependence on the lesion substrate. Thromb Haemostas 1995; 74: 552-9.
- 26 Chesebro JH, Badimon JJ, Badimon L, Fuster V. Arterial angioplasty : Injury, mural thrombus, and restenosis. In: The practice of Interventional Cardiology. Eds. Vogel JHK, King III SP. Ed. Mosby Year Book Inc.; (Chapter 45) 1993: 509-20.
- 27 Chesebro JH, Webster MW, Zoldhelyi P. et al. Thrombosis and restenosis after angioplasty. In: Coronary Restenosis. Eds. Robert S Schwartz. Ed. Blackwell Scientific Publications/EE. UU.; (Chapter 9) 1993: 219-37.
- 28 Badimon L, Alfon J, Royo T. et al. Cell biology of restenosis post-angioplasty. Z Kardiologie 1995; 84: 145-9.
- 29 Stary HC. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults. Arteriosclerosis 1989; 9: 1-19.
- 30 Wissler RW. USA multicenter study of the pathobiology of atherosclerosis in youth. Ann NY Acad Sci 1991; 623: 26-39.
- 31 Stary HC, Chandler AB, Dinsmore RE, Fuster V. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis: A report from the Committe on vascular lesions of the council on Atherosclerosis, American Heart Association. Circulation 1995; 92: 1355-74.
- 32 Faggiotto A, Ross R, Harker L. Studies of hypercholesterolemia in the nonhuman primate. I. Changes that lead to fatty streak formation. Arteriosclerosis 1984; 4: 323-40.
- 33 Brown M, Goldstein J. Atherosclerosis. Scavenging for receptors. Nature 1990; 343: 508-9.
- 34 Llorente-Cortés V, Martínez-González J, Badimon L. LDL receptor-related protein mediates uptake of aggregated LDL in human vascular smooth muscle cells. Arterrioscler Thromb Vascular Biol 2000; 20: 1572-9.
- 35 Badimon L, Chesebro JH, Badimon JJ. Thrombus formation on ruptured atheroschlerotic plaques and rethrombosis on evolving thrombi. Circulation 1992; 86 (suppl. III): III-74-85.
- 36 Badimon JJ, Badimon L, Galvez A. et al. High density lipoprotein plasma fractions inhibit aortic fatty streaks in cholesterol-fed rabbits. Lab Invest 1989; 60: 455-61.
- 37 Badimon JJ, Badimon L, Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest 1990; 85: 1234-41.
- 38 Arad Y, Badimon JJ, Badimon L. et al. Dehydroepiandrosterone feeding prevents aortic fatty streak formation and cholesterol accumulation in cholesterol-fed rabbit. Arteriosclerosis 1989; 9: 159-66.
- 39 Alfon J, Pueyo-Palazón C, Royo T, Badimon L. Effects of statins in thrombosis and aortic lesion development in a dyslipemic rabbit model. Thromb Haemost 1999; 81: 822-27.
- 40 Alfon J, Guasch JF, Berrozpe M, Badimon L. NOSII gene expression correlates with atherosclerotic intimal thickening. Preventive effects of HMG-CoA reductase inhibitors. Atherosclerosis 1999; 145: 325-31.
- 41 Aikawa M, Voglic SJ, Sugiyama S. et al. Dietary lipid lowering reduces tissue factor expression in rabbit atheroma. Circulation 1999; 100: 1215-22.
- 42 Barnes SE, Weinberg PD. Two patterns of lipid deposition in the cholesterolfed rabbits. Arterioscler Thromb Vascular Biol 1999; 19: 2376-86.
- 43 Malinov MR, Maruffo CA. Aortic atherosclerosis in free-ranging howler monkeys. Nature 1965; 206: 948-9.
- 44 Kaplan JR, Adams MR, Clarkson TB. et al. Psychosocial factors, sex differences, and atherosclerosis: lessons from animal models. Psychosom Med 1996; 58: 598-611.
- 45 Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation 1999; 99: 2192-217.
- 46 Royo T, Alfon J, Berrozpe M, Badimon L. Effect of gemfibrozil on peripheral atherosclerosis and platelet activation in a pig model of hyperlipidemia. Eur J Clin Invest 2000; 30: 843-52.
- 47 Pueyo Palazón C, Alfón J, Gaffney P. et al. Effects of reducing LDL and increasing HDL with Gemfibrozil in experimental coronary lesion development and thrombotic risk. Atherosclerosis 1998; 136: 333-45.
- 48 Fuster V, Badimon L, Rosemark JA. et al. Spontaneous and diet-induced coronary atherosclerosis in normal swine and swine with von Willebrand disease. Arteriosclerosis 1985; 5: 67-73.
- 49 Steele PM, Chesebro JH, Stanson AW. et al. Balloon angioplasty: Natural history of the pathophysiological response to injury in a pig model. Circulation Res 1985; 57: 105-12.
- 50 Badimon L, Steele P, Badimon JJ. et al. Aortic atherosclerosis in pigs with heterozygous von Willebrand disease. Comparison with homozygous von Willebrand and normal pigs. Arteriosclerosis 1985; 5: 366-70.
- 51 Fuster V, Badimon L, Badimon JJ. et al. Experimental approach to vascular disease in swine with von Willebrand’s disease. In: Swine in Biomedical Research. Ed. M. E. Tumbleson Plenum Publishing Corp.; 1986: 1527-42.
- 52 Zhang SH, Reddick RL, Piedrahita JA, Maeda N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 1992; 258: 468-71.
- 53 Carmeliet P, Moons L, Collen D. Mouse models of angiogenesis, arterial stenosis, atherosclerosis and hemostasis. Cardiovascular Res 1998; 39: 8-33.
- 54 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. (Part I) (Part II): New Eng. J Med 1992; 326: 242-50/310-8.
- 55 Badimon JJ, Fuster V, Chesebro JH, Badimon L. Coronary Atherosclerosis. Circulation 1993; 87: 3-16.
- 56 Ginsberg MH, Xiaoping D, O’Toole TE. et al. Platelet integrins. Thromb Haemost 1993; 70: 87-93.
- 57 Marcus A, Safier LB. Thromboregulation: multicellular modulation of platelet reactivity in hemostasis and thrombosis. FASEB J 1993; 7: 516-22.
- 58 Kieffer N, Phillips DR. Platelet membrane glycoproteins: functions in cellular interactions. Annu Rev Biol 1990; 6: 329-57.
- 59 Badimon L, Badimon JJ, Galvez A. et al. Influence of arterial damage and wall shear rate on platelet deposition. Ex vivo study in swine model. Arteriosclerosis 1986; 6: 312-20.
- 60 Badimon L, Badimon JJ. Mechanism of arterial thrombosis in non-parallel strealines: platelet grow at the apex of stenotic severely injured vessel wall. Experimental study in the pig model. J Clin Invest 1989; 84: 1134-44.
- 61 Lassila R, Badimon JJ, Vallabhajosula S, Badimon L. Dynamic monitoring of platelet deposition on severely damaged vessel wall in flowing blood. Effects of different stenosis on thrombus growth. Arteriosclerosis 1990; 10: 306-15.
- 62 Fernández-Ortiz A, Badimon JJ, Falk E. et al. Characterization of the relative thrombogenicity of atherosclerotic plaque components: implications for consequences of plaque rupture. J Am Coll Cardiol 1994; 23: 1562-9.
- 63 Toschi V, Gallo R, Lettino M. et al. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation 1997; 95: 594-9.
- 64 Badimon JJ, Berrozpe M, Lettino M. et al. Local inhibition of tissue factor reduces the thrombogenicity of disrupted human atherosclerotic plaques. Effects of TFPI on plaque thrombogenicity under flow conditions. Circulation 1999; 99: 1780-7.
- 65 Sánchez-Gómez S, Casani L, Vilahur G, Badimon L. FFR-rFVIIa inhibits thrombosis triggered by ruptured and eroded vessel wall. Thromb Haemost. 2001 (abstract cited in the CD-ROM of abstracts of the XVIIIth Congress of the ISTH).
- 66 Ghrib F, Leger P, Ezban M. et al. Anti-thrombotic and haemorrhagic effects of active site-inhibited factor VIIa in rats. Br J Haematol 2001; 112: 506-12.
- 67 Holst J, Kristensen AT, Kristensen HI. et al. Local application of recombinant active-site inhibited human clotting factor VIIa reduces thrombus weight and improves patency in a rabbit venous thrombosis model. Eur J Vasc Endovasc Surg 1998; 15: 515-20.
- 68 Badimon L, Fuster V, Chesebro JH, Badimon JJ. Kinetics of fibrinogen deposition on stenotic damaged vessel wall in arterial thrombosis. Thromb Haemost 1993; 69: 813.
- 69 Mailhac A, Badimon JJ, Fallon JT. et al. Effect of an eccentric severe stenosis on fibrin(ogen) deposition on severely damaged vessel wall in arterial thrombosis. Relative contribution of fibrin(ogen) and platelets. Circulation 1994; 90: 988-96.
- 70 Pueyo C, Royo T, Berrozpe M. et al. A fibrin (Bb chain) monolayer precedes platelets in the thrombotic response to atherosclerotic plaque rupture. Circulation 1995; 92: I-555.
- 71 Gruntzig A. Transluminal dilatation of coronary-artery stenosis. Lancet 1978; 1: 263.
- 72 Lam JYT, Chesebro JH, Steele PM. et al. Deep arterial injury during experimental angioplasty: Relation to a positive Indium-111 labeled platelet scintigram, quantitative platelet deposition and mural thrombosis. J Am Col Cardiol 1986; 8: 1380-6.
- 73 Lam JYT, Chesebro JH, Steele PM. et al. Is vasospasm related to platelet deposition? Relationship in a porcine preparation of arterial injury in vivo. Circulation 1987; 75: 243-8.
- 74 Heras M, Chesebro JH, Webster M. et al. Prevention of thrombosis by recombinant hirudin during arterial angioplasty in pigs: Comparison with heparin. J Am Col Cardiol 1989; 13: 77A.
- 75 Heras M, Chesebro JH, Penny WJ. et al. Effects of thrombin inhibition on the development of acute platelet-thrombus deposition during angioplasty in pigs: heparin versus recombinant hirudin, a specific thrombin inhibitor. Circulation 1989; 79: 657-65.
- 76 Heras M, Chesebro JH, Webster MWI. et al. Hirudin, heparin and, placebo during deep arterial injury in the pig: The in vivo role of thrombin in platelet mediated thrombosis. Circulation 1990; 82: 1476-84.
- 77 Badimon L, Turitto VT, Rosemark JA. et al. Characterization of a tubular flow chamber for studying platelet interaction with biologic and prosthetic materials: Deposition of Indium-111 labeled platelets on collagen, subendothelium and expanded polytetrafluoroethylene. J Lab Clin Medicine 1987; 110: 706-18.
- 78 Badimon L, Badimon JJ, Turitto VT, Fuster V. Role of von Willebrand Factor in platelet interaction expanded with an PTFE surface. Am Soc Artif Intern Organs 1987; 10: 621-5.
- 79 Badimon L, Badimon JJ, Rand J. et al. Platelet deposition on von Willebrand Factor deficient vessels extracorporeal perfusion studies in swine with von Willebrand’s disease using native and heparinized blood. J Lab Clin Med 1987; 110: 634-47.
- 80 Badimon L, Badimon JJ, Turitto VT. et al. Platelet thrombus formation on collagen type I a model of deep vessel injury. Influence of blood rheology, von Willebrand Factor and blood coagulation. Circulation 1988; 78: 1431-42.
- 81 Badimon L, Badimon JJ, Galvez A. et al. Platelet interaction with vessel wall and collagen in pigs with homozygous von Willebrand’s disease associated with abnormal collagen aggregation. Thromb Haemost 1989; 61: 57-64.
- 82 Badimon L, Badimon JJ, Turitto VT, Fuster V. Role of von Willebrand Factor in mediating platelet-vessel wall interaction at low shear rate; the importance of perfusion conditions. Blood 1989; 73: 961-7.
- 83 Badimon L, Badimon JJ, Turitto VT, Fuster V. Platelet interaction to prosthetic materials. Role of von Willebrand factor in platelet interaction to PTFE. J Biomat Applicat 1990; 5: 7-48.
- 84 Badimon L, Badimon JJ, Lassila R. et al. Thrombin regulation of platelet interaction with damaged vessel wall, and isolated collagen type I at arterial flow conditions in a porcine model : Effects hirudins, heparin and calcium chelation. Blood 1991; 78: 423-34.
- 85 Lam J, Chesebro JH, Steele P. et al. Antithrombotic therapy for deep arterial injury by angioplasty: Efficacy of common platelet inhibition compared with thrombin inhibition pigs. Circulation 1991; 84: 814-20.
- 86 Lam JYT, Chesebro JH, Badimon L, Fuster V. Exogenous prostacyclin decreases vasoconstriction but not platelet thrombus deposition after arterial injury. J Amer Col Cardiol 1993; 21: 488-92.
- 87 Merino A, Cohen M, Badimon JJ. et al. Synergistic action of severe wall injury and shear forces on thrombus formation in arterial stenosis: definition of a thrombotic shear rate threshold. J Am Coll Cardiol 1994; 24: 1091-4.
- 88 Badimon JJ, Badimon L, Turitto VT, Fuster V. Platelet deposition at high shear rates is enhanced by high plasma cholesterol levels. In vivo study in the rabbit model. Arterioscler Thromb 1991; 11: 395-402.
- 89 Alexopoulos D, Sanborn TA, Marmur JD. et al. Acute biological response to laser balloon angioplasty in the atherosclerotic rabbit. Laser Surg Med 1994; 14: 7-12.
- 90 Ngo TH, Declerck PJ. Immunological quantitation of rabbit plasminogen activator inhibitor-1 in biological samples:evidence that rabbit platelets do not contain PAI-I. Thromb Haemost 1999; 82: 1510-5.
- 91 Meyer BJ, Badimon JJ, Mailhac A. et al. Inhibition of growth of thrombus on fresh mural thrombus: targeting optimal therapy. Circulation 1994; 90: 2432-8.
- 92 Meyer B, Badimon JJ, Chesebro JH. et al. Dissolution of mural thrombus by specific thrombin inhibition with r-hirudin: comparison with Heparin and Aspirin. Circulation 1998; 97: 681-5.
- 93 Oliver MF, Davies MJ. The atheromatous lipid core. Eur Heart J 1998; 19: 16-8.
- 94 Felton CV, Crook D, Davies MJ, Oliver MF. Relation of plaque lipid composition and morphology to the stability of human aortic plaques. Atheroscler Thromb Vasc Dis 1997; 17: 1337-45.
- 95 Moreno PR, Falk E, Palacios IF. et al. Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation 1994; 90: 775-8.
- 96 Van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of intimal rupture or erosion of thrombosed coronary atheroschlerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994; 89: 36-44.
- 97 Fuster V, Badimon JJ, Badimon L. Clinical-pathological correlations of coronary disease progression and regression. Circulation 1992; 86: III-1-11.
- 98 Badimon JJ, Fuster V, Chesebro J, Badimon L. Coronary atherosclerosis. A multifactorial disease. Circulation 1993; 87 (suppl II): 3-16.
- 99 Toschi V, Gallo R, Lettino M. et al. Tissue Factor modulates the thrombogenicity of human atherosclerotic plaque. Circulation 1997; 95: 594-99.
- 100 Nemerson Y. Tissue factor and hemostasis. Blood 1998; 71: 1-8.
- 101 Nemerson Y. Tissue factor: Then and now. Thromb Haemost 1995; 74: 180-4.
- 102 McBane II RD, Miller RS, Hassinger NL. et al. Tissue Prothombin: Universal distribution in smooth muscle. Arterioscler Thromb Vasc Biol 1997; 17: 2430-6.
- 103 Annex BH, Denning SM, Channon KM. et al. Differential expression of tissue factor protein in directional atherectomy specimens from patients with stable and unstable coronary syndromes. Circulation 1995; 91: 619-22.
- 104 Giesen PLA, Rauch U, Bohrmann B. et al. Blood-borne tissue factor: Another view of thrombosis. Proc Nat Acad Sci. USA 1999; 96: 2311-5.
- 105 Badimon L, Martínez-González Royo T. et al. A sudden increase in plasma epinephrine levels transiently enhances platelet deposition on severely damaged arterial wall. Studies in a porcine model. Thromb Haemost 1999; 82: 1736-42.
- 106 Group SSSS. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-9.
- 107 Furberg CD, Byington RP, Crouse JR, Espeland MA. Pravastatin, lipids and major coronary events. Am J Cardiol 1994; 73: 1133-4.
- 108 Shepherd J, Cobbe SM, Ford I. et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. New Engl J Med 1995; 33: 1301-7.
- 109 Martínez González J, Badimon L. Human and porcine smooth muscle cells share similar proliferation dependence on the Mevalonate pathway. Implication for in vivo interventions in the porcine model. Eur J Clin Invest 1996; 26: 1023-32.
- 110 Huang CL, Cogan MG, Cragoc EJ, Ives HE. Thrombin activation of the Na+/H+ exchange in vascular smooth muscle cells. Evidence for a kinase c-independent pathway which is Ca2+-dependent and pertussis toxin-sensitive. J Biol Chem 1987; 262: 14134-40.
- 111 Weiss RH, Ives HE. Dissociation between activation of growth-related genes and mitogenic responses of neonatal vascular smooth muscle cells. Biochem Biophys Res Commun 1991; 181: 617-22.
- 112 Berk BC, Taubman MB, Cragoe Jr EJ. et al. Thrombin signal transduction mechanisms in rat vascular smooth muscle cells. J Biol Chem 1990; 265: 17334-40.
- 113 Berk BC, Taubman MB, Griendling KK. et al. Thrombin-stimulated events in cultured vascular smooth muscle cells. Biochem J 1991; 274: 799-805.
- 114 McNamara CA, Serembock IJ, Gimple LW. et al. Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor. J Clin Invest 1993; 91: 94-8.
- 115 Kanthou C, Kanse SM, Newman P. et al. Variability in the proliferative responsiveness of cultured human vascular smooth muscle cells to α-thrombin. Blood Coagul Fibrinolysis 1995; 6: 753-60.
- 116 Vu T-KH, Hung DT, Wheaton VI, Coughlin SR. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991; 64: 1057-68.
- 117 Hung DT, Vu T-KH, Nelken NA, Coughling SR. Thrombin induced events in non-platelet cells are mediated by the novel proteolytic mechanism defined by the platelet thrombin receptor. J Cell Biol 1992; 116: 827-32.
- 118 Bar-Shavit R, Benezra M, Eldor A. et al. Thrombin immobilized to extracellular matrix is a potent mitogen for vascular smooth muscle cells: nonenzimatic mode of action. Cell Reg 1990; 1: 453-63.
- 119 Daniel TO, Gibbs VC, Milfay DF. et al. Thrombin stimulates c-sis gene expression in microvascular endothelial cells. J Biol Chem 1986; 261: 9579-82.
- 120 Martínez-González J, Viñals M, Vidal F. et al. Mevalonate deprivation impairs IGF-I/insulin signaling in human vascular smooth muscle cells. Atherosclerosis 1997; 135: 213-23.
- 121 Varela O, Martínez-González J, Badimon L. Smooth muscle cells response to alpha-thrombin depends on its arterial origin: comparison among different species. Eur J Clin Invest 1998; 28: 313-23.
- 122 Royo T, Vidal M, Badimon L. Purification of the porcine platelets GP IIb/IIIa complex and propolypeptide of von Willebrand factor. Thromb Haemost 1998; 80: 302-9.
- 123 Pueyo C, Badimon JJ, Royo T. et al. A mimetic of the RGDF-peptide (arginine-glycine-aspartic acid-phenylalanine) blocks aggregation and flow-induced thrombosis on severely injured stenotic arterial wall. Effects on different animal models and in humans. Thromb Res 1996; 81: 101-12.
- 124 Cook NS, Bruttger O, Pally C, Hagenbach A. The effects of two synthetic glycoprotein IIb/IIIa antagonists, Ro 43-8857 and L-700,462, on platelet aggregation and bleeding in guinea-pigs and dogs: evidence that Ro 43-8857 is orally active. Thromb Haemost 1993; 70: 838-47.
- 125 Royo T, Vidal M, Badimon L. Porcine platelet von Willebrand Antigen II (vW AgII): Inhibitory effect on collagen induced aggregation and comparative distribution with human platelets. Thromb Haemost 1998; 80: 677-85.
- 126 Rand JH, Badimon L, Gordon RE. et al. Distribution of von Willebrand Factor in porcine intima varies with blood vessel type and location. Arteriosclerosis 1987; 7: 287-91.
- 127 Royo T, Badimon L. The propolypeptide of von Willebrand factor (pp-vWF) is immunolocalized in the golgi apparatus of porcine aortic endothelial cells. Thromb Haemost. 1999 suppl: 583a (abstr.).
- 128 Castelló A, Cases-Langhoff C, Martínez-González J, Badimon L. De-differentiated smooth muscle cells in human coronary atherosclerotic lesions express a new mitogen-inducible nuclear orphan receptor gene. Eur Heart J 1999; 20 suppl 357a (abstr.).
- 129 Rodriguez-Sinovas C, Martínez-González J, Sánchez-Gómez S, Badimon L. LDL downregulate CYP51 in vascular endothelial cells and in the arterial wall through a SREBP-2 dependent mechanism. Circ Res 2001; 88: 268-74.