The ‘PAI-1 paradox’ in vascular remodelling

Summary

Vascular remodelling isa complex phenomenon associated with restructuring of the vessel wall as a consequence of disruption of vascular homeostasis. Alterations of the vascular wall have been linked to a variety of cardiovascular disorders including atherosclerosis, vascular injury and pulmonary hypertension. Plasminogen activator inhibitor-1 (PAI-1) is a member of the serpin (serine proteinase inhibitor) family and acts as an important inhibitor of fibrinolysis by interfering with the plasminogen system. In addition to its anti-fibrinolytic effects, PAI-1 appears to modulate cellular responses linked to vascular remodelling. Since PAI-1 levels have been shown to be altered in various disorders associated with vascular remodelling of the systemic and pulmonary vascular bed, this serpin may playa pivotal role in the pathogenesis of these diseases.

Keywords

Plasminogen activator inhibitors - atherosclerosis - restenosis - remodelling - pulmonary hypertension

^* These authors contributed equally.

• References

• 1 Pinsky DJ. et al. Hypoxia and modification of the endothelium: implications for regulation of vascular homeostatic properties. Semin Cell Biol 1995; 06: 283-294.
• 2 Schoenhagen P. et al. Arterial remodelling and coronary artery disease: the concept of “dilated” versus “obstructive” coronary atherosclerosis. J Am Coll Cardiol 2001; 38: 297-306.
• 3 Gibbons GH, Dzau VJ. The emerging concept of vascular remodelling. N Engl J Med 1994; 330: 1431-1438.
• 4 Touyz RM. Intracellular mechanisms involved in vascular remodelling of resistance arteries in hypertension: role of angiotensin II. Exp Physiol 2005; 90: 449-455.
• 5 Mandegar M. et al. Cellular and molecular mechanisms of pulmonary vascular remodeling: role in the development of pulmonary hypertension. Microvasc Res 2004; 68: 75-103.
• 6 Humbert M. et al. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004; 43 (Suppl. 12) 13S-24S.
• 7 Spronk HM. et al. Blood coagulation and the risk of atherothrombosis: a complex relationship. Thromb J 2004; 02: 12.
• 8 Fay WP. et al. Vascular functions of the plasminogen activation system. Arterioscler Thromb Vasc Biol 2007; 27: 1231-1237.
• 9 Martorell L. et al. Thrombin and protease-activated receptors (PARs) in atherothrombosis. Thromb Haemost 2008; 99: 305-315.
• 10 Herkert O. et al. Insights into the redox control of blood coagulation: role of vascular NADPH oxidasederived reactive oxygen species in the thrombogenic cycle. Antioxid Redox Signal 2004; 06: 765-776.
• 11 Fay WP. Plasminogen activator inhibitor 1, fibrin, and the vascular response to injury. Trends Cardiovasc Med 2004; 14: 196-202.
• 12 Schleef RR, Loskutoff DJ. Fibrinolytic system of vascular endothelial cells. Role of plasminogen activator inhibitors. Haemostasis 1988; 18: 328-341.
• 13 Kruithof EK. Plasminogen activator inhibitors--a review. Enzyme 1988; 40: 113-121.
• 14 Alessi MC, Juhan-Vague I. Contribution of PAI-1 in cardiovascular pathology. Arch Mal Coeur Vaiss 2004; 97: 673-678.
• 15 Weisberg AD. et al. Pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor-1 attenuates angiotensin II/salt-induced aortic remodelling. ArteriosclerThromb Vasc Biol 2005; 25: 365-371.
• 16 Aso Y. Plasminogen activator inhibitor (PAI)-1 in vascular inflammation and thrombosis. Front Biosci 2007; 12: 2957-2966.
• 17 Chen Y. et al. Augmentation of proliferation of vascular smooth muscle cells by plasminogen activator inhibitor type 1. Arterioscler Thromb Vasc Biol 2006; 26: 1777-1783.
• 18 Chen Y. et al. Inhibition of apoptosis and caspase-3 in vascular smooth muscle cells by plasminogen activator inhibitor type-1. J Cell Biochem 2004; 92: 178-188.
• 19 Rossignol P. et al. Plasminogen activation: a mediator of vascular smooth muscle cell apoptosis in atherosclerotic plaques. J Thromb Haemost 2006; 04: 664-670.
• 20 Sobel BE. Increased plasminogen activator inhibitor-1 and vasculopathy. A reconcilable paradox. Circulation 1999; 99: 2496-2498.
• 21 Blasi F, Carmeliet P. uPAR: a versatile signalling orchestrator. Nat Rev Mol Cell Biol 2002; 03: 932-943.
• 22 Lindahl TL. et al. Stability of plasminogen activator inhibitor 1 (PAI-1). Thromb Haemost 1989; 62: 748-751.
• 23 Andreasen PA. et al. Plasminogen activator inhibitor from human fibrosarcoma cells binds urokinase-type plasminogen activator, but not its proenzyme. J Biol Chem 1986; 261: 7644-7651.
• 24 Manchanda N, Schwartz BS. Interaction of singlechain urokinase and plasminogen activator inhibitor type 1. J Biol Chem 1995; 270: 20032-20035.
• 25 Herz J. et al. LDL receptor-related protein internalizes and degrades uPA-PAI-1 complexes and is essential for embryo implantation. Cell 1992; 71: 411-421.
• 26 Olson D. et al. Internalization of the urokinaseplasminogen activator inhibitor type-1 complex is mediated by the urokinase receptor. J Biol Chem 1992; 267: 9129-9133.
• 27 Kjoller L. et al. Plasminogen activator inhibitor-1 represses integrin-and vitronectin-mediated cell migration independently of its function as an inhibitor of plasminogen activation. Exp Cell Res 1997; 232: 420-429.
• 28 Cubellis MV. et al. Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PAI-1. EmboJ 1990; 09: 1079-1085.
• 29 Laufs S. et al. Urokinase-receptor (u-PAR): an essential player in multiple games of cancer:a review on its role in tumor progression, invasion, metastasis, proliferation/dormancy, clinical outcome and minimal residual disease. Cell Cycle 2006; 05: 1760-1771.
• 30 Nykjaer A. et al. Purified alpha 2-macroglobulin receptor/LDL receptor-related protein binds urokinase. plasminogen activator inhibitor type-1 complex. Evidence that the alpha 2-macroglobulin receptor mediates cellular degradation of urokinase receptorbound complexes. J Biol Chem 1992; 267: 14543-14546.
• 31 Zhang JC. et al. The low density lipoprotein receptor-related protein/alpha2-macroglobulin receptor regulates cell surface plasminogen activator activity on human trophoblast cells. J Biol Chem 1998; 273: 32273-32280.
• 32 Leksa V. et al. The N terminus of mannose 6-phosphate/insulin-like growth factor 2 receptor in regulation of fibrinolysis and cell migration. J Biol Chem 2002; 277: 40575-40582.
• 33 Nykjaer A. et al. Mannose 6-phosphate/insulin-like growth factor-II receptor targets the urokinase receptor to lysosomes via a novel binding interaction. J Cell Biol 1998; 141: 815-828.
• 34 Hoyer-Hansen G. et al. The intact urokinase receptor is required for efficient vitronectin binding: receptor cleavage prevents ligand interaction. FEBS Lett 1997; 420: 79-85.
• 35 Sidenius N, Blasi F. Domain 1 of the urokinase receptor (uPAR) is required for uPAR-mediated cell binding to vitronectin. FEBS Lett 2000; 470: 40-46.
• 36 Declerck PJ. et al. Purification and characterization of a plasminogen activator inhibitor 1 binding protein from human plasma. Identification as a multimeric form of S protein (vitronectin). J Biol Chem 1988; 263: 15454-15461.
• 37 Seiffert D. et al. Serum-derived vitronectin influences the pericellular distribution of type 1 plasminogen activator inhibitor. J Cell Biol 1990; 111: 1283-1291.
• 38 Preissner KT, Seiffert D. Role of vitronectin and its receptors in haemostasis and vascular remodelling. Thromb Res 1998; 89: 1-21.
• 39 Dellas C, Loskutoff DJ. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease. Thromb Haemost 2005; 93: 631-640.
• 40 Deng G. et al. Structural and functional analysis of the plasminogen activator inhibitor-1 binding motif in the somatomedin B domain of vitronectin. J Biol Chem 1996; 271: 12716-21273.
• 41 Czekay RP. et al. Direct binding of occupied urokinase receptor (uPAR) to LDL receptor-related protein is required for endocytosis of uPAR and regulation of cell surface urokinase activity. Mol Biol Cell 2001; 12: 1467-1479.
• 42 Reilly CF, Hutzelmann JE. Plasminogen activator inhibitor-1 binds to fibrin and inhibits tissue-type plasminogen activator-mediated fibrin dissolution. J Biol Chem 1992; 267: 17128-17135.
• 43 Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature 1996; 383: 441-443.
• 44 Kanse SM. et al. Reciprocal regulation of urokinase receptor (CD87)-mediated cell adhesion by plasminogen activator inhibitor-1 and protease nexin-1. J Cell Sci 2004; 117: 477-485.
• 45 Lijnen HR. Pleiotropic functions of plasminogen activator inhibitor-1. J Thromb Haemost 2005; 03: 35-45.
• 46 Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med 2004; 351: 1655-1665.
• 47 Welsh CH. et al. Coagulation and fibrinolytic profiles in patients with severe pulmonary hypertension. Chest 1996; 110: 710-717.
• 48 Hoeper MM. et al. Plasma coagulation profiles in patients with severe primary pulmonary hypertension. Eur Respir J 1998; 12: 1446-1449.
• 49 Christ G. et al. Impairment of the plasmin activation system in primary pulmonary hypertension: evidence for gender differences. Thromb Haemost 2001; 86: 557-562.
• 50 Koh SC. et al. Plasminogen activators t-PA, u-PA and its inhibitor (PAI) in normal males and females. Thromb Haemost 1991; 66: 581-585.
• 51 Lang IM. et al. Parallel analysis of tissue-type plasminogen activator and type 1 plasminogen activator inhibitor in plasma and endothelial cells derived from patients with chronic pulmonary thromboemboli. Circulation 1994; 90: 706-712.
• 52 Huber K. et al. Fibrinogen, t-PA, and PAI-1 plasma levels in patients with pulmonary hypertension. Am J Respir Crit Care Med 1994; 150: 929-933.
• 53 Lang IM. et al. Elevated expression of urokinaselike plasminogen activator and plasminogen activator inhibitor type 1 during the vascular remodelling associated with pulmonary thromboembolism. Arterioscler Thromb Vasc Biol 1998; 18: 808-815.
• 54 Lassegue B, Griendling KK. Reactive oxygen species in hypertension; An update. Am J Hypertens 2004; 17: 852-860.
• 55 Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 2005; 115: 500-508.
• 56 Madamanchi NR. et al. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol 2005; 25: 29-38.
• 57 Djordjevic T, Gorlach A. Urotensin-II in the lung: a matter for vascular remodelling and pulmonary hypertension?. Thromb Haemost 2007; 98: 952-962.
• 58 Bonello S. et al. Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site. Arterioscler Thromb Vasc Biol 2007; 27: 755-761.
• 59 Kouri FM. et al. Plasminogen activator inhibitor type 1 inhibits smooth muscle cell proliferation in pulmonary arterial hypertension. Int J Biochem Cell Biol 2008; 40: 1872-1882.
• 60 Itoh T. et al. C-type natriuretic peptide ameliorates monocrotaline-induced pulmonary hypertension in rats. Am J Respir Crit Care Med 2004; 170: 1204-1211.
• 61 Sage E. et al. Endothelial cell apoptosis in chronically obstructed and reperfused pulmonary artery. Respir Res 2008; 09: 19.
• 62 Dimova EY. et al. Oxidative stress and hypoxia: implications for plasminogen activator inhibitor-1 expression. Antioxid Redox Signal 2004; 06: 777-791.
• 63 Kietzmann T. et al. Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes. Blood 1999; 94: 4177-4185.
• 64 Pinsky DJ. et al. Coordinated induction of plasminogen activator inhibitor-1 (PAI-1) and inhibition of plasminogen activator gene expression by hypoxia promotes pulmonary vascular fibrin deposition. J Clin Invest 1998; 102: 919-928.
• 65 Levi M. et al. Deficiency of urokinase-type plasminogen activator-mediated plasmin generation impairs vascular remodelling during hypoxia-induced pulmonary hypertension in mice. Circulation 2001; 103: 2014-2020.
• 66 Sawa H. et al. Potentiation by hypercholesterolemia of the induction of aortic intramural synthesis of plasminogen activator inhibitor type 1 by endothelial injury. Circ Res 1993; 73: 671-680.
• 67 Carmeliet P. et al. Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice. Circulation 1997; 96: 3180-3191.
• 68 de Waard V. et al. Plasminogen activator inhibitor1 and vitronectin protect against stenosis ina murine carotid artery ligation model. Arterioscler Thromb Vasc Biol 2002; 22: 1978-1983.
• 69 Hasenstab D. et al. Local plasminogen activator inhibitor type 1 overexpression in rat carotid artery enhances thrombosis and endothelial regeneration while inhibiting intimal thickening. Arterioscler Thromb Vasc Biol 2000; 20: 853-859.
• 70 DeYoung MB. et al. Plasminogen activator inhibitor type 1 increases neointima formation in balloon-injured rat carotid arteries. Circulation 2001; 104: 1972-1971.
• 71 Schafer K. et al. Plasminogen activator inhibitor-1 from bone marrow-derived cells suppresses neointimal formation after vascular injury in mice. Arterioscler Thromb Vasc Biol 2006; 26: 1254-1259.
• 72 Ploplis VA, Castellino FJ. Attenuation of neointima formation following arterial injury in PAI-1 deficient mice. Ann NY Acad Sci 2001; 936: 466-468.
• 73 Witkowski P. et al. A DNA enzyme against plasminogen activator inhibitor-type 1 (PAI-1) limits neointima formation after angioplasty in an obese diabetic rodent model. J Cardiovasc Pharmacol 2007; 50: 633-640.
• 74 Suzuki J. et al. The effects of pharmacological PAI-1 inhibition on thrombus formation and neointima formation after arterial injury. Expert Opin Ther Targets 2008; 12: 783-794.
• 75 Otsuka G. et al. Transforming growth factor beta1 induces neointima formation through plasminogen activator inhibitor-1-dependent pathways. Arterioscler Thromb Vasc Biol 2006; 26: 737-743.
• 76 Kawasaki T. et al. Mouse carotid artery ligation induces platelet-leukocyte-dependent luminal fibrin, required for neointima development. Circ Res 2001; 88: 159-166.
• 77 Lijnen HR. et al. Neointima formation and thrombosis after vascular injury in transgenic mice overexpressing plasminogen activator inhibitor-1 (PAI-1). J Thromb Haemost 2004; 02: 16-22.
• 78 Schafer K. et al. Different mechanisms of increased luminal stenosis after arterial injury in mice deficient for urokinase-or tissue-type plasminogen activator. Circulation 2002; 106: 1847-1852.
• 79 Lupu F. et al. Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb 1993; 13: 1090-1100.
• 80 Schneiderman J. et al. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci USA 1992; 89: 6998-7002.
• 81 Olofsson BO. et al. Evidence for increased levels of plasminogen activator inhibitor and tissue plasminogen activator in plasma of patients with angiographically verified coronary artery disease. Eur HeartJ 1989; 10: 77-82.
• 82 Schafer K. et al. Enhanced thrombosis in atherosclerosis-prone mice is associated with increased arterial expression of plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 2003; 23: 2097-2103.
• 83 Schneider DJ. et al. Attenuation of neointimal vascular smooth muscle cellularity in atheroma by plasminogen activator inhibitor type 1 (PAI-1). J Histochem Cytochem 2004; 52: 1091-1099.
• 84 Luttun A. et al. Lack of plasminogen activator inhibitor-1 promotes growth and abnormal matrix remodelling of advanced atherosclerotic plaques in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2002; 22: 499-505.
• 85 Zhu Y. et al. Plasminogen activator inhibitor type 1 enhances neointima formation after oxidative vascular injury in atherosclerosis-prone mice. Circulation 2001; 103: 3105-3110.
• 86 Sjoland H. et al. Atherosclerosis progression in LDL receptor-deficient and apolipoprotein E-deficient mice is independent of genetic alterations in plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 2000; 20: 846-852.
• 87 Stefansson S. et al. Inhibition of angiogenesis in vivo by plasminogen activator inhibitor-1. J Biol Chem 2001; 276: 8135-8141.
• 88 Drinane M. et al. The anti-angiogenic activity of rPAI-1(23) inhibits fibroblast growth factor-2 functions. J Biol Chem 2006; 281: 33336-33344.
• 89 Proia RR. et al. The effect of endothelial cell overexpression of plasminogen activator inhibitor-1 on smooth muscle cell migration. J Vasc Surg 2002; 36: 164-171.
• 90 Bar-Shavit R. et al. Thrombin immobilized to extracellular matrix is a potent mitogen for vascular smooth muscle cells: nonenzymatic mode of action. Cell Regul 1990; 01: 453-463.
• 91 Underwood PA. et al. Human endothelial cells grow poorly on vitronectin: role of PAI-1. J Cell Biochem 2001; 82: 98-109.
• 92 Stefansson S. et al. The contributions of integrin affinity and integrin-cytoskeletal engagement in endothelial and smooth muscle cell adhesion to vitronectin. J Biol Chem 2007; 282: 15679-15689.
• 93 Czekay RP. et al. Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol 2003; 160: 781-791.
• 94 Michel JB. Anoikis in the cardiovascular system: known and unknown extracellular mediators. Arterioscler Thromb Vasc Biol 2003; 23: 2146-2154.
• 95 Balsara RD. et al. A novel function of plasminogen activator inhibitor-1 in modulation of the AKT pathway in wild-type and plasminogen activator inhibitor-1-deficient endothelial cells. J Biol Chem 2006; 281: 22527-22536.
• 96 Chen SC. et al. Plasminogen activator inhibitor-1 inhibits prostate tumor growth through endothelial apoptosis. Mol Cancer Ther 2008; 07: 1227-1236.
• 97 Quax PH. et al. Adenoviral expression of a urokinase receptor-targeted protease inhibitor inhibits neointima formation in murine and human blood vessels. Circulation 2001; 103: 562-569.
• 98 Bajou K. et al. The plasminogen activator inhibitor PAI-1 controls in vivo tumor vascularization by interaction with proteases, not vitronectin. Implications for antiangiogenic strategies. J Cell Biol 2001; 152: 777-784.
• 99 Isogai C. et al. Plasminogen activator inhibitor-1 promotes angiogenesis by stimulating endothelial cell migration toward fibronectin. Cancer Res 2001; 61: 5587-5594.
• 100 Devy L. et al. The pro-or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. Faseb J 2002; 16: 147-154.
• 101 Otsuka G. et al. Mechanisms of TGF-beta1-induced intimal growth: plasminogen-independent activities of plasminogen activator inhibitor-1 and heterogeneous origin of intimal cells. Circ Res 2007; 100: 1300-1307.
• 102 Loskutoff DJ. et al. Regulation of cell adhesion by PAI-1. Apmis 1999; 107: 54-61.
• 103 Degryse B. et al. The low density lipoprotein receptor-related protein isa motogenic receptor for plasminogen activator inhibitor-1. J Biol Chem 2004; 279: 22595-22604.
• 104 Peng L. et al. Endogenous vitronectin and plasminogen activator inhibitor-1 promote neointima formation in murine carotid arteries. Arterioscler Thromb Vasc Biol 2002; 22: 934-939.
• 105 Konstantinides S. et al. Plasminogen activator inhibitor-1 and its cofactor vitronectin stabilize arterial thrombi after vascular injury in mice. Circulation 2001; 103: 576-583.
• 106 Eitzman DT. et al. Hyperlipidemia promotes thrombosis after injury to atherosclerotic vessels in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2000; 20: 1831-1834.
• 107 Mulligan Kehoe MJ. et al. A truncated plasminogen activator inhibitor-1 protein blocks the availability of heparin-binding vascular endothelial growth factor A isoforms. J Biol Chem 2002; 277: 49077-49089.