Mice deficient in tissue factor demonstrate attenuated intimal hyperplasia in response to vascular injury and decreased smooth muscle cell migration

Robert T. Pyo; Yuichiro Sato; Nigel Mackman; Mark B. Taubman

doi:10.1160/TH04-02-0122

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(03): 451-458
DOI: 10.1160/TH04-02-0122

Theme Issue Article

Schattauer GmbH

Mice deficient in tissue factor demonstrate attenuated intimal hyperplasia in response to vascular injury and decreased smooth muscle cell migration

Robert T. Pyo

¹The Cardiovascular Institute and Department of Medicine, Mount Sinai Medical Center, New York, New York

,

Yuichiro Sato

²Department of Immunology, The Scripps Research Institute, La Jolla, California

,

Nigel Mackman

²Department of Immunology, The Scripps Research Institute, La Jolla, California

,

Mark B. Taubman

¹The Cardiovascular Institute and Department of Medicine, Mount Sinai Medical Center, New York, New York

³Department of Medicine, University of Rochester, Rochester, New York, USA

› Author Affiliations

Abstract

Summary

Tissue factor (TF) is the primary initiator of the coagulation cascade and is thought to play a key role in the generation of arterial thrombosis. Recent studies have suggested that TF mediates inflammatory processes in the arterial wall and may be an important regulator of intimal hyperplasia. We have employed genetically engineered mice (mTF^−/−/hTF⁺) with markedly diminished TF activity (≈1% normal levels) to examine the role of TF in mediating the response to arterial injury. mTF^−/−/hTF⁺ displayed a marked reduction in intimal hyperplasia (46% decrease in intimal area, 60% decrease in intimal/medial ratio) in response to femoral artery injury when compared to wild type controls. The decreased intimal hyperplasia seen in low TF mice was noted in a model of vascular injury not associated with significant thrombosis, suggesting that it may be mediated by non-procoagulant properties of TF. Smooth muscle cells from mTF^−/−/hTF⁺ mice grew normally in response to serum, but exhibited a marked defect in cell migration in a modified Boyden chamber assay. In contrast, there was no difference in platelet derived growth factorinduced migration, suggesting that the effect of TF on smooth muscle cell migration is agonist dependent. These data suggest that TF may mediate intimal hyperplasia by regulating smooth muscle cell migration.

Keywords

Vascular smooth muscle - cell migration - arterial injury - genetically altered mice - tissue factor

Full Text

References

References
1 Nemerson Y. Tissue factor: then and now. Thromb Haemost 1995; 74: 180-4.
2 Rapaport SI, Rao LV. The tissue factor pathway: how it has become a “prima ballerina”. Thromb Haemost 1995; 74: 7-17.
3 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.
4 Hatakeyama K, Asada Y, Marutsuka K. et al. Localization and activity of tissue factor in human aortic atherosclerotic lesions. Atherosclerosis 1997; 133: 213-9.
5 Marmur JD, Thiruvikraman SV, Fyfe BS. et al. Identification of active tissue factor in human coronary atheroma. Circulation 1996; 94: 1226-32.
6 Moreno PR, Bernardi VH, Lopez-Cuellar J. et al. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation 1996; 94: 3090-7.
7 Thiruvikraman SV, Guha A, Roboz J. et al. In situ localization of tissue factor in human atherosclerotic plaques by binding of digoxigenin-labeled factors VIIa and X. Lab Invest 1996; 75: 451-61.
8 Wilcox JN, Smith KM, Schwartz SM. et al. Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque. Proc Natl Acad Sci USA 1989; 86: 2839-43.
9 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992; 326: 310-8.
10 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med 1992; 326: 242-50.
11 Edgington TS, Mackman N, Brand K. et al. The structural biology of expression and function of tissue factor. Thromb Haemost 1991; 66: 67-79.
12 Taubman MB. Thrombosis, arteriosclerosis, and coronary artery disease. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U. ed. Williams’ Hematology. New York: McGraw Hill; 2001: 1743-62.
13 Pawlinski R, Fernandes A, Kehrle B. et al. Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction. Proc Natl Acad Sci U S A 2002; 99: 15333-8.
14 Marmur JD, Rossikhina M, Guha A. et al. Tissue factor is rapidly induced in arterial smooth muscle after balloon injury. J Clin Invest 1993; 91: 2253-9.
15 Pawashe AB, Golino P, Ambrosio G. et al. A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries. Circ Res 1994; 74: 56-63.
16 Speidel CM, Eisenberg PR, Ruf W. et al. Tissue factor mediates prolonged procoagulant activity on the luminal surface of ballooninjured aortas in rabbits. Circulation 1995; 92: 3323-30.
17 Gertz SD, Fallon JT, Gallo R. et al. Hirudin reduces tissue factor expression in neointima after balloon injury in rabbit femoral and porcine coronary arteries. Circulation 1998; 98: 580-7.
18 Jang IK, Gold HK, Leinbach RC. et al. Antithrombotic effect of a monoclonal antibody against tissue factor in a rabbit model of platelet-mediated arterial thrombosis. Arterioscler Thromb 1992; 12: 948-54.
19 Courtman DW, Schwartz SM, Hart CE. Sequential injury of the rabbit abdominal aorta induces intramural coagulation and luminal narrowing independent of intimal mass: extrinsic pathway inhibition eliminates luminal narrowing. Circ Res 1998; 82: 996-1006.
20 Golino P, Ragni M, Cirillo P. et al. Antithrombotic effects of recombinant human, active site-blocked factor VIIa in a rabbit model of recurrent arterial thrombosis. Circ Res 1998; 82: 39-46.
21 Harker LA, Hanson SR, Wilcox JN. et al. Antithrombotic and antilesion benefits without hemorrhagic risks by inhibiting tissue factor pathway. Haemostasis 1996; 26 (Suppl. 01) 76-82.
22 Asada Y, Hara S, Tsuneyoshi A. et al. Fibrinrich and platelet-rich thrombus formation on neointima: recombinant tissue factor pathway inhibitor prevents fibrin formation and neointimal development following repeated balloon injury of rabbit aorta. Thromb Haemost 1998; 80: 506-11.
23 Roque M, Reis ED, Fuster V. et al. Inhibition of tissue factor reduces thrombus formation and intimal hyperplasia after porcine coronary angioplasty. J Am Coll Cardiol 2000; 36: 2303-10.
24 Ross R. Growth regulatory mechanisms and formation of the lesions of atherosclerosis. Ann N Y Acad Sci 1995; 748: 1-4 discussion 4-6.
25 Signore PE, Machan LS, Jackson JK. et al. Complete inhibition of intimal hyperplasia by perivascular delivery of paclitaxel in ballooninjured rat carotid arteries. J Vasc Interv Radiol 2001; 12: 79-88.
26 Roque M, Reis ED, Cordon-Cardo C. et al. Effect of p27 deficiency and rapamycin on intimal hyperplasia: in vivo and in vitro studies using a p27 knockout mouse model. Lab Invest 2001; 81: 895-903.
27 Jang Y, Guzman LA, Lincoff AM. et al. Influence of blockade at specific levels of the coagulation cascade on restenosis in a rabbit atherosclerotic femoral artery injury model. Circulation 1995; 92: 3041-50.
28 Oltrona L, Speidel CM, Recchia D. et al. Inhibition of tissue factor-mediated coagulation markedly attenuates stenosis after ballooninduced arterial injury in minipigs. Circulation 1997; 96: 646-52.
29 Han X, Girard TJ, Baum P. et al. Structural requirements for TFPI-mediated inhibition of neointimal thickening after balloon injury in the rat. Arterioscler Thromb Vasc Biol 1999; 19: 2563-7.
30 Zoldhelyi P, Chen ZQ, Shelat HS. et al. Local gene transfer of tissue factor pathway inhibitor regulates intimal hyperplasia in atherosclerotic arteries. Proc Natl Acad Sci U S A 2001; 98: 4078-83.
31 Singh R, Pan S, Mueske CS. et al. Tissue factor pathway inhibitor deficiency enhances neointimal proliferation and formation in a murine model of vascular remodelling. Thromb Haemost 2003; 89: 747-51.
32 Parry GC, Erlich JH, Carmeliet P. et al. Low levels of tissue factor are compatible with development and hemostasis in mice. J Clin Invest 1998; 101: 560-9.
33 Roque M, Fallon JT, Badimon JJ. et al. Mouse model of femoral artery denudation injury associated with the rapid accumulation of adhesion molecules on the luminal surface and recruitment of neutrophils. Arterioscler Thromb Vasc Biol 2000; 20: 335-42.
34 Poon M, Marx SO, Gallo R. et al. Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest 1996; 98: 2277-83.
35 Carmeliet P, Mackman N, Moons L. et al. Role of tissue factor in embryonic blood vessel development. Nature 1996; 383: 73-5.
36 Clowes AW, Clowes MM. Kinetics of cellular proliferation after arterial injury. II. Inhibition of smooth muscle growth by heparin. Lab Invest 1985; 52: 611-6.
37 Petersen LC, Freskgard P, Ezban M. Tissue factor-dependent factor VIIa signaling. Trends Cardiovasc Med 2000; 10: 47-52.
38 Siegbahn A, Johnell M, Rorsman C. et al. Binding of factor VIIa to tissue factor on human fibroblasts leads to activation of phospholipase C and enhanced PDGF-BB-stimulated chemotaxis. Blood 2000; 96: 3452-8.
39 Cunningham MA, Romas P, Hutchinson P. et al. Tissue factor and factor VIIa receptor/ ligand interactions induce proinflammatory effects in macrophages. Blood 1999; 94: 3413-20.
40 Camerer E, Rottingen JA, Gjernes E. et al. Coagulation factors VIIa and Xa induce cell signaling leading to up- regulation of the egr-1 gene. J Biol Chem 1999; 274: 32225-33.
41 Petersen LC, Thastrup O, Hagel G. et al. Exclusion of known protease-activated receptors in factor VIIa-induced signal transduction. Thromb Haemost 2000; 83: 571-6.
42 Versteeg HH, Hoedemaeker I, Diks SH. et al. Factor VIIa/tissue factor-induced signaling via activation of Src-like kinases, phosphatidylinositol 3-kinase, and Rac. J Biol Chem 2000; 275: 28750-6.
43 Camerer E, Huang W, Coughlin SR. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci U S A 2000; 97: 5255-60.
44 Sato Y, Asada Y, Marutsuka K. et al. Tissue factor pathway inhibitor inhibits aortic smooth muscle cell migration induced by tissue factor/factor VIIa complex. Thromb Haemost 1997; 78: 1138-41.
45 Major CD, Santulli RJ, Derian CK. et al. Extracellular mediators in atherosclerosis and thrombosis: lessons from thrombin receptor knockout mice. Arterioscler Thromb Vasc Biol 2003; 23: 931-9.
46 Coughlin SR. Protease-activated receptors in the cardiovascular system. Cold Spring Harb Symp Quant Biol 2002; 67: 197-208.
47 Patterson C, Stouffer GA, Madamanchi N. et al. New tricks for old dogs: nonthrombotic effects of thrombin in vessel wall biology. Circ Res 2001; 88: 987-97.
48 Bretschneider E, Braun M, Fischer A. et al. Factor Xa acts as a PDGF-independent mitogen in human vascular smooth muscle cells. Thromb Haemost 2000; 84: 499-505.
49 Gasic GP, Arenas CP, Gasic TB. et al. Coagulation factors X, Xa, and protein S as potent mitogens of cultured aortic smooth muscle cells. Proc Natl Acad Sci U S A 1992; 89: 2317-20.
50 Herbert J, Bono F, Herault J. et al. Effector protease receptor 1 mediates the mitogenic activity of factor Xa for vascular smooth muscle cells in vitro and in vivo . J Clin Invest 1998; 101: 993-1000.
51 Ko FN, Yang YC, Huang SC. et al. Coagulation factor Xa stimulates platelet-derived growth factor release and mitogenesis in cultured vascular smooth muscle cells of rat. J Clin Invest 1996; 98: 1493-501.
52 McLean K, Schirm S, Johns A. et al. FXa- Induced Responses in Vascular Wall Cells are PAR-Mediated and Inhibited by ZK-807834. Thromb Res 2001; 103: 281-97.
53 Nicholson AC, Nachman RL, Altieri DC. et al. Effector cell protease receptor-1 is a vascular receptor for coagulation factor Xa. J Biol Chem 1996; 271: 28407-13.
54 Bono F, Schaeffer P, Herault JP. et al. Factor Xa activates endothelial cells by a receptor cascade between EPR- 1 and PAR-2. Arterioscler Thromb Vasc Biol 2000; 20: E107-12.
55 Schaeffer P, Mares AM, Dol F. et al. Coagulation factor Xa induces endothelium-dependent relaxations in rat aorta. Circ Res 1997; 81: 824-8.
56 Riewald M, Kravchenko VV, Petrovan RJ. et al. Gene induction by coagulation factor Xa is mediated by activation of protease-activated receptor 1. Blood 2001; 97: 3109-16.
57 Ruf W, Mueller BM. Tissue factor signaling. Thromb Haemost 1999; 82: 175-82.
58 Muller M, Albrecht S, Golfert F. et al. Localization of tissue factor in actin-filament-rich membrane areas of epithelial cells. Exp Cell Res 1999; 248: 136-47.
59 Ott I, Fischer EG, Miyagi Y. et al. A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280. J Cell Biol 1998; 140: 1241-53.
60 Bromberg ME, Konigsberg WH, Madison JF. et al. Tissue factor promotes melanoma metastasis by a pathway independent of blood coagulation. Proc Natl Acad Sci U S A 1995; 92: 8205-9.
61 Bromberg ME, Sundaram R, Homer RJ. et al. Role of tissue factor in metastasis: functions of the cytoplasmic and extracellular domains of the molecule. Thromb Haemost 1999; 82: 88-92.
62 Bromberg ME, Bailly MA, Konigsberg WH. Role of protease-activated receptor 1 in tumor metastasis promoted by tissue factor. Thromb Haemost 2001; 86: 1210-4.
63 Mueller BM, Ruf W. Requirement for binding of catalytically active factor VIIa in tissue factor-dependent experimental metastasis. J Clin Invest 1998; 101: 1372-8.
64 Giesen PL, Rauch U, Bohrmann B. et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci U S A 1999; 96: 2311-5.
65 Key NS, Slungaard A, Dandelet L. et al. Whole blood tissue factor procoagulant activity is elevated in patients with sickle cell disease. Blood 1998; 91: 4216-23.
66 Mallat Z, Benamer H, Hugel B. et al. Elevated levels of shed membrane microparticles with procoagulant potential in the peripheral circulating blood of patients with acute coronary syndromes. Circulation 2000; 101: 841-3.
67 Santucci RA, Erlich J, Labriola J. et al. Measurement of tissue factor activity in whole blood. Thromb Haemost 2000; 83: 445-54.
68 Suefuji H, Ogawa H, Yasue H. et al. Increased plasma tissue factor levels in acute myocardial infarction. Am Heart J 1997; 134: 253-9.
69 te Velthuis H, van den Brink HG, de Groot ER. et al. Soluble tissue factor in plasma. Thromb Haemost. 1999 Abstract.
70 Fukuda C, Iijima K, Nakamura K. Measuring tissue factor (factor III) activity in plasma. Clin Chem 1989; 35: 1897-900.
71 Soejima H, Ogawa H, Yasue H. et al. Heightened tissue factor associated with tissue factor pathway inhibitor and prognosis in patients with unstable angina. Circulation 1999; 99: 2908-13.
72 Combes V, Simon AC, Grau GE. et al. In vitro generation of endothelial microparticles and possible prothrombotic activity in patients with lupus anticoagulant. J Clin Invest 1999; 104: 93-102.
73 Mallat Z, Hugel B, Ohan J. et al. Shed membrane microparticles with procoagulant potential in human atherosclerotic plaques: a role for apoptosis in plaque thrombogenicity. Circulation 1999; 99: 348-53.
74 Satta N, Toti F, Feugeas O. et al. Monocyte vesiculation is a possible mechanism for dissemination of membrane-associated procoagulant activities and adhesion molecules after stimulation by lipopolysaccharide. J Immunol 1994; 153: 3245-55.
75 Bogdanov VY, Balasubramanian V, Hathcock J. et al. Alternatively spliced human tissue factor: a circulating, soluble, thrombogenic protein. Nat Med 2003; 09: 458-62.
76 Ferns GA, Raines EW, Sprugel KH. et al. Inhibition of neointimal smooth muscle accumulation after angioplasty by an antibody to PDGF. Science 1991; 253: 1129-32.
77 Schmitz U, Thommes K, Beier I. et al. Lysophosphatidic acid stimulates p21-activated kinase in vascular smooth muscle cells. Biochem Biophys Res Commun 2002; 291: 687-91.
78 Ai S, Kuzuya M, Koike T. et al. Rho-Rho kinase is involved in smooth muscle cell migration through myosin light chain phosphorylation-dependent and independent pathways. Atherosclerosis 2001; 155: 321-7.