Angiogenesis pp 263-282 | Cite as

Cellular and Molecular Effects of Thrombin in the Vascular System

  • Chryso Kanthou
  • Vijay Vir Kakkar
  • Omar Benzakour
Part of the NATO ASI Series book series (NSSA, volume 298)


Two distinct physiological processes lead to the development of new blood vessels: vasculogenesis and angiogenesis [reviewed by Risau, 1997]. Whereas vasculogenesis is restricted to embryonic development and consists in the differentiation of mesodermal precursor cells into endothelial cells followed by their organisation into the capillary plexus, angiogenesis is the formation of new capillaries from pre-existing blood vessels and takes place both during prenatal and adult life. Angiogenesis can occur under both physiological and pathological conditions such as during wound healing and solid tumour development. Moreover, intra-arterial angiogenesis is evident in atherosclerotic plaques and in recanalised thrombi [reviewed by Eisenstein, 1991]. The cellular and molecular events that lead to angiogenesis are not as yet fully elucidated but are known to include (i) breakdown of the extracellular matrix and of basement membrane of pre-existing blood vessels; (ii) the migration and proliferation of endothelial cells; (iii) production of extracellular matrix allowing the reconstitution of the basement membrane; (iv) recruitment of pericytes and vascular smooth muscle cells (VSMC) to the newly formed blood vessel.


Vascular Smooth Muscle Cell Mitogenic Effect Thrombin Receptor Potent Mitogen Human Vascular Smooth Muscle Cell 
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. Andersson, M., Ostman, A., Westermark, B., Heldin, C-H., 1994. Characterisation of the retention motif in the C-terminal part of the long splice form of platelet-derived growth factor A-chain. J. Biol. Chem. 269: 926–930.PubMedGoogle Scholar
  2. Bachhuber, B.G., Sarembock, I.J., Gimble L.W., and Owens, G.K., 1997. Alpha thrombin induces transforming growth factor beta-1 mRNA and protein in cultred vascular smooth muscle cels via a proteolytically activated recetpro. J. Vasc. Res. 34:41–48.PubMedGoogle Scholar
  3. Bahou, W.F., Coller, B.S., Potter, C.L., Norton K.J., Kutok J.L., and Goligorsky, M.S., 1993. The thrombin receptor extracellular domain contains sites crucial for peptide ligand-induced activation. J. Clin. Invest. 91: 1405–1413.PubMedCrossRefGoogle Scholar
  4. Bar-Shavit, R., Benezra, D., Eldor, A., Hy-Am, E., Fenton, J.W., II, and Vlodavsky, I., 1990. Thrombin immobilized to extracellular matrix is a potent mitogen for vascular smooth muscle cells: Nonenzymatic mode of action. Cell Regul. 1: 453–463.PubMedGoogle Scholar
  5. Bar-Shavit, R., Benezra, M., Sabbah, V., Dejana, E., Vlodavsky, I., and Wilner, G.D., 1992. Functional domains in thrombin outside the catalytic site. In: Berliner, L.J., (ed) “Thrombin: structure and function” Plenum Press: NY and London, pp. 315–350Google Scholar
  6. Barger, A., Beeuwkes, R., Lainey, L., Silverman, K., 1984. Hypothesis: vasa vasorum and neovascularization of human coronary arteries. N. Eng. J. Med. 310: 175–177.CrossRefGoogle Scholar
  7. Belloni, P.N., Carney, D.H., and Nicolson, G.L., 1992. Organ-derived endothelial cells express differential responsiveness to thrombin and other growth factors. Microvasc. Res. 43:20–45.PubMedCrossRefGoogle Scholar
  8. Benezra, M., Vlodavsky, I., Bar-Shavit, R., 1993. Prothrombin conversion to thrombin by plasminogen activator residing in the subendothelial extracellular matrix. Semin. Thromb. Haemost. 19:405–411.CrossRefGoogle Scholar
  9. Benzakour, O., and Kanthou, C., 1996. Cellular and molecular events in atherogenesis: basis for pharmacological and gene therapy approaches to restenosis. Cell Pharmacol. 3:7–22.Google Scholar
  10. Benzakour, O., Kanthou, C., Lupu, F., Dennehy, U., Goodwin, C., Scully, M.F., Kakkar, V.V., and Cooper, D.N., 1955. Prothrombin cleavage by human vascular smooth muscle cells: a potential alternative pathqway to the coagulation cascade. J. Cell Biochem. 59: 514–528.CrossRefGoogle Scholar
  11. Berk, B.C., Taubman, M.B., Cragoe, E.J., Fenton, J.W., II, and Greindling K.K., 1991. Thrombin-stimulated events in cultured vascular smooth-muscle cells. Biochem. J. 274: 799–805PubMedGoogle Scholar
  12. Brass, L.F., 1992. Homologous desensitisation of HEL cell thrombin receptors: distinguishable roles for proteolysis and phosphorylation. J. Biol. Chem. 267: 6044–6050.PubMedGoogle Scholar
  13. Brass, L.F., Laposata, F., Banga, H.S., and Rittenhouse, S.E., 1986. Regulation of the phosphoinositide hydrolysis pathway in thrombin-stimulated platelets by a pertussis toxin-sensitive guanine nucleotide-binding protein. J. Biol. Chem. 261: 16833–16847.Google Scholar
  14. Brass, L.F., Pizarro, S., Ahuja, M., Belmonte, E., Stadel, J., and Hoxie, J.A., 1994. Changes in the structure and function of the human thrombin receptor during receptor activation, internalisation, and recycling. J. Biol. Chem. 269: 2943–2952.PubMedGoogle Scholar
  15. Brass, L.F., Vassallo R.R., Belmonte, E., Ahuja, M., Cichowski, K., and Hoxie, J.A., 1992. Structure and function of the human platelet thrombin receptor. Studies using monoclonal antibodies directed against a defined domain within the receptorN terminus. J. Biol. Chem. 267: 13795–13798.PubMedGoogle Scholar
  16. Carney, D.H. 1992. Postclotting cellular effects of thrombin mediated by interactions with high affinity thrombin receptors. In: Berliner, L.J. (ed) “Thrombin: structure and function”. Plenum Press: NY and London, pp. 351–396.Google Scholar
  17. Chen, L.B., and Buchanan, J.M., 1975. Mitogenic activity of blood components. Thrombin and Prothrombin. Proc. Natl. Acad. Sci. USA 72: 131–135.PubMedCrossRefGoogle Scholar
  18. Clapham, D.E., and Neer, E.J., 1993. New roles for G-protein bg-dimers in transmembrane signalling. Nature 365: 403–406.PubMedCrossRefGoogle Scholar
  19. Connolly, A., Ishihara, H., Kahn, M., Farese, R.V. Jr., and Coughlin S.R., 1996. Role of thrombin receptor in development and evidence for a second receptor. Nature 381:516–519.PubMedCrossRefGoogle Scholar
  20. Davies, M.J., Bland, M.J., Hangartner, W.R., Angelini, A., and Thomas, A.C., 1989. Factors influencing the presence of acute coronary thrombi in sudden ischaemic death. Eur. Heart. J. 10: 203–208.PubMedGoogle Scholar
  21. Eisenstein, R., 1991. Angiogenesis in arteries. Pharmacol Ther. 49: 1–19.PubMedCrossRefGoogle Scholar
  22. Esmon, C.T., 1993. Cell-mediated events that control blood coagulation and vascular injury. Annu. Rev. Cell Biol 9: 1–26.PubMedCrossRefGoogle Scholar
  23. Garcia, J.G.N., Aschner, J.L., and Malik, A.B., 1992. Regulation of thrombin-induced endothelial barrier dysfunction and prostaglandin synthesis. In: Berliner, L.J., (ed) “Thrombin: structure and fonction” Plenum Press: NY and London, pp. 397–430.Google Scholar
  24. Gerrity, R.G., and Cliff, W.J., 1975. The aortic tunica media of the develooping rat. I. Quantitative stereologic and biochemical analysis. Laborat. Invest. 32: 585–600.PubMedGoogle Scholar
  25. Gerszten, R.E., Chen, J., Ishii, M., Ishii, K., Wang, I., Nanevicz, T., Turck, C.W., Vu, T-K.H., and Coughin S.R., 1994. Specificity of the thrombin receptor for agonist peptide is defined by its extracellular surface. Nature 368: 648–651.PubMedCrossRefGoogle Scholar
  26. Haralabopoulos, G.C., Grant, D.S., Kleinman, H.K., Maragoudakis, M.E., 1997. Thrombin promotes endothelial cell alignment in matrigel in vitro and angiogenesis in vivo. Am. J. Physiol. (in press)Google Scholar
  27. Hatton, M.W., Moar, S.L., and Richardson, M., 1989. Deendothelialization in vivo initiates a thrombogenic reaction at the rabbit aorta surface. Correlation of uptake of fibrinogen and antithrombin III with thrombin generation by the exposed sub endothelium. Am. J. Pathol. 135: 499–508.PubMedGoogle Scholar
  28. Herbert, J-M., Dupuy, E., Laplace, M-C., Zini, J-M., Bar-Shavt, R., and Tobelem G., 1994. Thrombin induces endothelial cell growth via both a proteolytic and a non-proteolytic pathway. Biochem. J. 303: 227–231.PubMedGoogle Scholar
  29. Herbert, J-M., Lamarche, I., Prabonnaud, V., Dol, F., and Gauthier, T., 1994. Tissue type plasminogen activator is a potent mitogen for human aortic smooth muscle cells. J. Biol. Chem. 269: 3076–3080.PubMedGoogle Scholar
  30. Houck, K.A., Ferrara, N., Winer, I., Cachianes, G., Li, B., and Leung, D.W., 1992. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 5: 1806–1814.CrossRefGoogle Scholar
  31. Hoxie, J.A., Ahuja, M., Belmonte, E., Pizarro, S., Parton, R., and Brass L.F., 1993. Internalisation and recycling of activated thrombin receptors. J. Biol. Chem. 268: 13756–13763.PubMedGoogle Scholar
  32. Huang, C.L., and Ives, H.E., 1987. Growth inhibition by protein kinase C late in mitogenesis. Nature 329: 849–850.PubMedCrossRefGoogle Scholar
  33. Hung, D.T., Wong, Y.H., Vu, T-K.H., and Coughlin, S.R., 1992. The cloned platelet thrombin receptor couples to at least two distinct effectors to stimulate phosphoinositide hydrolysis and inhibit adenylyl cyclase. J. Biol Chem. 267: 20831–20834.PubMedGoogle Scholar
  34. Ishihara, H., Connolly, A.J., Zeng, D., Kahn, M.L., Zheng Y.W., Timmons, C., Tram, T., and Coughlin S.R., 1997. Protease-activated receptor 3 is a second thrombin receptor in humans. Nature 386: 502–506.PubMedCrossRefGoogle Scholar
  35. Ishii, K., Chen J., Ishii, M., Koch, W.J., Freedman, N.J., Lefkowitz, R.J., and Coughlin S.R., 1994. Inhibition of thrombin receptor signalling by a G-protein coupled receptor kinase: functional specificity among G-protein coupled receptor kinases. J. Biol. Chem. 269: 1125–1130.PubMedGoogle Scholar
  36. Ishii, K., Hein, L., Kobilka, B., and Coughlin, S.R., 1993. Kinetics of thrombin receptor cleavage on intact cells. Relation to signaling. J. Biol. Chem. 268: 9780–9786.PubMedGoogle Scholar
  37. Kaetzel, D.M., Coyne, D.W., and Fenstermaker, R.A., 1993. Transcriptional control of the platelet derived growth factor subunit genes. Biofactors 4: 71–81.PubMedGoogle Scholar
  38. Kahan, C., Seuwen, K., Meloche, S., and Pouyssegur, J., 1992. Coordinate, biphasic activation of p44 mitogen-activated protein kinase and S6 kinase by growth factors in hamster fibroblasts. J. Biol. Chem. 267: 13369–13375.PubMedGoogle Scholar
  39. Kanse, S.M., Benzakour, O., Kanthou, C., Kost, C., Lijnen, R., and Preissner, K.T., 1997. Urokinase-type plasminogen activator stimulates hyman vascular smooth muscle cell proliferation. Atheroscl. Thromb. Vasc. Biol., (in press).Google Scholar
  40. Kanthou, C., and Benzakour, O., 1995. Cellular effects of thrombin and their signalling pathways. Cell Pharmacol. 2: 293–302.Google Scholar
  41. Kanthou, C., Benzakour, O., Patel, G., Deadman, J., Kakkar, V.V., and Lupu, F., 1995a. Thrombin receptor activating peptide (TRAP) stimulates mitogenesis, c-fos and PDGF-A gene expression in human vascular smooth muscle cells. Thromb. Haemost. 74: 1340–1347.PubMedGoogle Scholar
  42. Kanthou, C., Kanse, S.M., Kakkar, V.V., and Benzakour, O., 1996. Involvement of pertussis toxin sensitive and insensitive G proteins in thormbin signalling on cultured human vacular smooth muscle cells. Cell. Signall. 8: 59–66.CrossRefGoogle Scholar
  43. Kanthou, C., Kanse, S.M., Newman, P., Kakkar, V.V., and Benzakour, O., 1995b. Structural domains of thormbin involved in the induction of mitogenesis in cultured human vascular smooth muscle cells. Blood Coag. Fibr. 6: 634–642.CrossRefGoogle Scholar
  44. Kanthou, C., Parry, G., Wijelath, E., Kakkar, V.V., and Demoliou-Mason, C., 1992. Thrombin-induced proliferation and expression of platelet-derived growth factor-A chain gene in human vascular smooth muscle cells. FEBS Lett. 314: 134–148.CrossRefGoogle Scholar
  45. Ku, P.T., and D’Amore, P.A., 1995. Regulation of basic fibroblast growth factor (bFGF) gene and protein expression following its release from sublethally injured endothelial cells. J. Cell Biochem. 58: 328–343.PubMedCrossRefGoogle Scholar
  46. Li, X.N., Varma, V.K., Parks, J.M., Benza, R.L., Koons J.C., Grammer, JR., Grenett, H., Tabengwa, E.M., and Booyse F.M., 1995. Thombin decreases the urokinase receptor and surface localized fibrinolysis in cultured endothelial cells. Arteroscler. Thromb. 15: 410–419.CrossRefGoogle Scholar
  47. Lin, L-L., Wartmann, M., Lin, A.Y., Knopf, J.L, Scih, A.A., and Davis R.J., 1993. cPLA2 is phosphorylated and activated by MAP kinase. Cell 72: 269–278.PubMedCrossRefGoogle Scholar
  48. Lombardi, D.M.M., Reidy, M.A., and Schwartz, S.M., 1991. Methodologic considerations important in the accurate quntitation of aortic smooth muscle cell replication in the normal rat. Am. J. Pathol. 138: 441–446.PubMedGoogle Scholar
  49. Magnaldo, I., Pouyssegur, J., and Paris, S., 1988. Thrombin exerts a dual effect on stimulated adenylate cyclase in hamster fibroblasts: an inhibition via a GTP-binding protein and a potentiation via activation of protein kinase C. Biochem. J. 253: 711–719.PubMedGoogle Scholar
  50. Majesky, M.W., Reidy, M.A., Bowen-Pope, D.F., Hart, C.E., Wilcox, J.N., and Schwartz, S.M., 1990. PDGF ligand and receptor gene expression during repair or arterial injury. J. Cell Biol. 111:2149–2158.PubMedCrossRefGoogle Scholar
  51. Mann, K.G., 1994. Prothrombin and Thrombin. In Colman, R.W., Hirsh, J., Marder, V.J., and Salzman, E.W., (eds): “Haemostasis and Thrombosis: Basic Principles and Clinical Practice”. Lippincott Company: Philadelphia, pp. 184–199.Google Scholar
  52. Maragoudakis, M., E., 1996. The role of thormbinin angiogenesis. In: “Molecular, Celluar and Clinical Aspects of Angiogenesis”‘Ed. Maragoudakis, Plenum Press, pp 115–124.CrossRefGoogle Scholar
  53. McNamara, C.A., Sarembock, I.J., Gimple, L.W., Fenton, J.W., II, Coughlin, S.R., and Owens, G.K., 1993. Thrombin stimulates proliferation of cultured rat aortic smooth muscle cells by a proteolytically activated receptor. J. Clin. Invest. 91: 94–98.PubMedCrossRefGoogle Scholar
  54. Molloy, C.J., Pawlowski, J.E., Taylor, D.S., Turner, C.E., Weber, H., Peluso, M., and Seiler, S.M., 1996. Thrombin receptor activation elicits rapid protein tyrosine phosphorylatin and stimulation of the raf-1/MAP kinase pathway preceding delayed mitogenesis in cultured rat aortic smooth muscle cells. J. Clin. Invest. 97: 1173–1183.PubMedCrossRefGoogle Scholar
  55. Ngaiza, J.R., and Jaffe, E.A., 1991. A 14 amino acid peptide derived from the amino terminus of the cleaved thrombin receptor elevates intracellular calcium and stimulates prostacycline production by human endothelial cells. Biochem. Biophys. Res. Commun. 179: 1656–1661.PubMedCrossRefGoogle Scholar
  56. Noda-Heiny, H., Fujii, S., and Sobel, B.E., 1993. Induction of vascular smooth muscle cell expression of plasminogen activator inhibitor-1 by thrombin. Circ. Res. 72: 36–43.PubMedCrossRefGoogle Scholar
  57. Obberghen-Schilling, E.V., and Pouyssegur, J., 1993. a-Thrombin receptors and growth signalling. Semin. Thromb. Haem. 19: 378–385.CrossRefGoogle Scholar
  58. Okada, S.S., Grobmyer, S.R., and Barnathan E.S., 1996. Contrasting effects of plasminogen activators, urokinase receptor and LDL receptor-related protein on smooth muscle cell migration and invation. Arterioscler. Thromb. Vasc. Biol. 16: 1269–1276.PubMedCrossRefGoogle Scholar
  59. Okazaki, H., Majesky, M.W., Harker, L.A., and Schwartz, S.M., 1992. Regulation of platelet-derived growth factor ligand and receptor gene expression by a-thrombin in vascular smooth muscle cells. Circ. Res. 71: 1285–1293.PubMedCrossRefGoogle Scholar
  60. Pearson, J.D., 1994. Endothelial cell function and thrombosis. Baillieres Clinical Haematology 7: 441–452.CrossRefGoogle Scholar
  61. Pepper, M.S., Montesano, R., Mandriota, S., Orci, L., and Vassalli, J-D., 1996. Angiogenesis: a paradigm for balanced extracellular proteolysis during cell migratio and morphogenesis. Enzyme Protein 49: 138–162.PubMedGoogle Scholar
  62. Rade, J.J., Schulick, A.H., Virmani, R., and Dichek, D.A., 1996. Local adenoviral-mediated expression of recombinant hirudin reduces neointima formation after arterial injury. Nature Med. 2: 293–298.PubMedCrossRefGoogle Scholar
  63. Raines, E.W., and Ross, R., 1992. Compartmentalisation of PDGF on extracellular binding sites dependent on exon 6 encoded sequences. J. Cell Biol. 116: 553–543.CrossRefGoogle Scholar
  64. Rasmussen, U.B., Vouret-Craviari, V., Jallat, S., Schlesinger, Y., Pages, G., Pavirani, A., Lecocq, J-P., Pouyssegur, J., and Van Obberghen-Schilling, E., 1991. cDNA cloning and expression of a hamster a-thrombin receptor coupled to Ca2+ mobilization. FEBS Lett 288: 123–128.PubMedCrossRefGoogle Scholar
  65. Reuning, U., Little S.P., Dixon, E.P., and Bang, N.U. 1994. Effect of thormbi, the thrombin receptor activation peptide, and other mitogens on vascular smooth muscle cell urokinase receptor mRNA levels. Blood 84: 3700–3708.PubMedGoogle Scholar
  66. Risau, W., 1997. Mechanisms of angiogenesis. Nature 386: 671–674.PubMedCrossRefGoogle Scholar
  67. Ross, R., 1993. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362: 801–809.PubMedCrossRefGoogle Scholar
  68. Scarpati, E.M., and DiCorleto, P.E., 1996. Identification of a thrombin response element in the human platelet-derived growth factor B-chain (c-sis) promoter. J. Biol. Chem. 271: 3025–3032.PubMedCrossRefGoogle Scholar
  69. Schaeffer, P., Riera, E., Dupuy, E., and Herbert J.M., 1997. Non-proteolytic activation of thro thrombin receptor promotes human umbilical vein endothelial cell growth but not intracellular Ca2+ prostacyclin or permeablility. Biochem. Pharmacol. 53: 487–491.PubMedCrossRefGoogle Scholar
  70. Sekiya, F., Usui, H., Inoue, K., Fukudome K., Morita, T., 1994. Activation of prothrombin by a novel membrane-associated protease. J. Biol. Chem. 269: 32441–32445.PubMedGoogle Scholar
  71. Scihi, N., and Brookes, M., 1971. Ultrastructure of the blood vessels in the chick allantois and chorioallantois. J. Anat. 109: 1–5.Google Scholar
  72. Shankar, R, de la Motte, C.A., Poptic, E.J., and Dicorletto, P.E., 1994. Thrombin receptor-activating peptides differentially stimulate platelet-derived growth factor production, monocytic cell adhesion, and E-selectin expression in human umbilical vein endothelial cells. J. Biol. Chem. 269: 13936–13941.PubMedGoogle Scholar
  73. Sternberg, J., Redin, W.R., Warner, W.S., and Carney, D.H., 1993. The Role of thrombin and the thrombin receptor activating peptide (TRAP-508) in initiation of tissue repair. Thromb. Haemost. 70: 158–162.Google Scholar
  74. Taipale, J., Koli, K., and Keski-Oja, J., 1992. Release of transforming growth factor-b1 from the pericellular matrix of cultured fibroblasts and fibrosarcoma cells by plasmin and thrombin. J. Biol. Chem. 267: 25378.PubMedGoogle Scholar
  75. Taparelli, C., Metternich, R., Ehrhardt, C., and Cook, N.S., 1993. Synthetic low-molecular weight thrombin inhibitors: molecular design and pharmacological profile. TIPS 14: 366–376.Google Scholar
  76. Trejo, J.A., Connolly, A.J., and Coughlin, S.R., 1996. The cloned thrombin receptor is necessary and sufficient for activtion of mitogen-activated protein kinase and mitogenesis in mouse lung fibroblasts. J. Biol. Chem. 271: 21536–21541.PubMedCrossRefGoogle Scholar
  77. Tsopanoglou, N.E., Pipili-Synetos, E., and Maragoudakis, M.E., 1993. Thrombin promotes angiogenesis by a mechanism independent of fibrin formation. Am. J. Physiol. 264: C1302–1307.Google Scholar
  78. Vlodavsky, I., Folkman, J., Sullivan, R., Fridman, R., Ishai-Michaeli, R., Sasse, J., and Klagsbrun M., 1987. Endothelial cell-derived basic fibroblast growth factor: Synthesis and deposition into subendothelial extracellular matrix. Proc. Natl. Acad. Sci. USA 84: 2292–2296.PubMedCrossRefGoogle Scholar
  79. Vouret-Craviari, V., Grall, D., Chambard, J-C., Rasmussen U.B., Pouyssegur, J., and Van Obberghen-Schilling, E., 1995. Post translational and activation-dependent modifications of the G-protein coupled thrombin receptor. J. Biol. Chem. 270: 8367–8372.PubMedCrossRefGoogle Scholar
  80. Vouret-Craviari, V., Van Obberghen-Schilling, E., Scimeca J-C., Van Obberghen, E., and Pouyssegur J., 1993. Differential activation of p44mapk (ERK1) by a-thrombin and synthetic receptor peptide agonists. Biochem. J. 289: 209–214.PubMedGoogle Scholar
  81. Vouret-Craviari, V., Van Obberghen-Schilling, E., Rasmusse, U.B., Paviran, A., Lecocq, J-P., and Pouyssegur, J., 1992. Synthetic a-thrombin receptor peptides activate G-protein coupled signalling pathways but are unable to induce mitogenesis. Mol. Biol. Cell 3: 95–102.PubMedGoogle Scholar
  82. Vu, T-K.H., Hung, D.T., Wheaton, V.I., and Coughlin, S.R., 1991. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64: 1057–1068.PubMedCrossRefGoogle Scholar
  83. Walters, T.K., Gorog, D.A., and Wood, R.F.M., 1994. Thrombin generation following arterial injury is a critical initiating event in the pathogenesis of the proliferative stages of the atherosclerotic process. J. Vase. Res. 31: 173–177.CrossRefGoogle Scholar
  84. Wang, H.S., Li, F., Runge, M.S., and Chaikof, E.L., 1997. Endothelial cells exhibit differential chemokinetic and mitogenic responsiveness to alpha thormbin. J. Surg. Res. 68: 139–144.PubMedCrossRefGoogle Scholar
  85. Weiss, R.H., and Maduri, M., 1993. The mitogenic effect of thrombin in vascular smooth muscle cells is largely due to basic fibroblast growth factor. J. Biol. Chem. 268: 5724–5727.PubMedGoogle Scholar
  86. Weitz, J.I., Hudoba, M., Massel, D., Maraganore, J.M., and Hirsh, J., 1990. Clotbound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin Ill-independent inhibitors. J. Clin. Invest. 86: 385–391.PubMedCrossRefGoogle Scholar
  87. Wilcox, J.N., Rodriguez, J., Subramanian, R., Ollerenshaw, J., Zhong, C., Hayzer, D.J., Horaist, C., Hanson, S.R., Lumsden A., Salam, T.A., Kelly, A.B., Harker, LA., and Runge, M., 1994. Characterisation of thrombin receptor expression during vascular lesion formation. Circ. Res. 75: 1029–1039.PubMedCrossRefGoogle Scholar
  88. Wojta, J., Gallicchio, M., Zoellner, H., Hufnagl, P., Last, K., Filonzi, E.L., Binder, B.R., Hamilton, J.A., and McGrath, K., 1993. Thrombin stimulates expression of tissue-type plasminogen activator and plasminogen activator inhibitor type 1 in cultured human vascular smooth muscle Cells. Thromb. Haemost. 70: 469–474.PubMedGoogle Scholar
  89. Woolkalis, M.J., and Brass, L.F., 1994. Thrombin receptor cleavage and intemalisation in human umbilical endothelial cells. FASEB J.. 8: A 1385.Google Scholar
  90. Zoldhelyi, P., Bichler, J., Owen, W.G., Grill, D.E., Fuster, V., Mruk, J.S., Chesebro, J.H., 1994. Persistent thrombin generation in humans during specific thrombin inhibition with hirudin. Circulation 90: 2671–2678.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Chryso Kanthou
    • 1
  • Vijay Vir Kakkar
    • 1
  • Omar Benzakour
    • 1
  1. 1.Thrombosis Research InstituteEmmanuel Kaye BuildingLondonUK

Personalised recommendations