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The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis

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The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis International Journal of Molecular Sciences Review The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis Yosuke Kanno Department of Clinical Pathological Biochemistry, Faculty of Pharmaceutical Science, Doshisha Women’s College of Liberal Arts, 97-1 Kodo Kyo-tanabe, Kyoto 610-0395, Japan; [email protected]; Tel.: +81-0774-65-8629 Received: 19 November 2018; Accepted: 29 January 2019; Published: 31 January 2019 Abstract: Systemic sclerosis (SSc) is a connective tissue disease of autoimmune origin characterized by vascular dysfunction and extensive fibrosis of the skin and visceral organs. Vascular dysfunction is caused by endothelial cell (EC) apoptosis, defective angiogenesis, defective vasculogenesis, endothelial-to-mesenchymal transition (EndoMT), and coagulation abnormalities, and exacerbates the disease. Fibrinolytic regulators, such as plasminogen (Plg), plasmin, α2-antiplasmin (α2AP), tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1), and angiostatin, are considered to play an important role in the maintenance of endothelial homeostasis, and are associated with the endothelial dysfunction of SSc. This review considers the roles of fibrinolytic factors in vascular dysfunction of SSc. Keywords: Fibrinolytic regulators; SSc; vascular dysfunction 1. Introduction Systemic sclerosis (SSc) is an autoimmune rheumatic disease of unknown etiology that is characterized by vascular dysfunction and fibrosis of the skin and visceral organs as well as peripheral circulatory disturbance [1]. This process usually occurs over many months and years and can lead to organ dysfunction or death. In SSc, vascular disorders are observed from early onset to the appearance of late complications and affect various organs, including the lungs, kidneys, heart, and digital arteries, and exacerbate the disease [2]. Microvascular disorders, such as Raynaud’s phenomenon, telangiectasias, and digital ulcers, frequently occur in SSc patients [2–4]. In contrast, macrovascular disorders, such as those of the coronary arteries, are rarely involved in SSc [2,5,6]. In SSc, the vascular dysfunction is caused by vascular and endothelial cell (EC) injury, defective angiogenesis, defective vasculogenesis, endothelial-to-mesenchymal transition (EndoMT), vascular tone alteration, and coagulation abnormalities [7], and is associated with abnormalities in the immune system, such as T-cells, B-cells, mast cells, macrophages infiltration, immune activation, and auto-antibody production, as well as abnormalities in the extracellular matrix (ECM) metabolism, such as myofibroblast differentiation, ECM over-production, and the inhibition of ECM degradation. These abnormalities may influence each other and lead to the development of pulmonary arterial hypertension (PAH) and fibrosis [2] (Figure1). However, the detailed mechanism underlying the relationship between “fibrosis” and “vascular dysfunction” remains unclear. It is reported that vasculopathy occurs in various mice, as urokinase-type plasminogen activator receptor (uPAR)-deficient mice develop EC apoptosis and severe loss of micro-vessels [8]. Caveolin-1-deficient mice show dilated cardiomyopathy and pulmonary hypertension [9]. Caveolin-1 is associated with the internalization and degradation of transforming growth factor-β (TGF-β) receptors and regulates TGF-β signaling [10]. Fli1-deficient mice show a disorganized dermal vascular network with greatly compromised vessel integrity and Int. J. Mol. Sci. 2019, 20, 619; doi:10.3390/ijms20030619 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, x 2 of 18 Int. J. Mol. Sci. 2019, 20, 619 2 of 19 increased vessel permeability and impaired vascular homeostasis. Fli1 is associated with the expression of platelet/endothelial cell adhesion molecule (PECAM)-1, platelet derived growth factor increased vessel permeability and impaired vascular homeostasis. Fli1 is associated with the expression (PDGF), and sphingosine-1-phosphate receptors (S1PR) [11]. Fos-related antigen-2 (Fra-2) transgenic of platelet/endothelial cell adhesion molecule (PECAM)-1, platelet derived growth factor (PDGF), mice develop microvascular and proliferative vasculopathy, and pulmonary vascular lesions and sphingosine-1-phosphate receptors (S1PR) [11]. Fos-related antigen-2 (Fra-2) transgenic mice resembling SSc-associated PAH [12]. However, while these factors may play a critical role in the onset develop microvascular and proliferative vasculopathy, and pulmonary vascular lesions resembling of SSc-associated vascular disorders, the detailed mechanism underlying their involvement is SSc-associated PAH [12]. However, while these factors may play a critical role in the onset of unclear. SSc-associated vascular disorders, the detailed mechanism underlying their involvement is unclear. Figure 1. Vascular dysfunction in systemic sclerosis (SSc). In SSc, the vascular dysfunction is caused by vascularFigure and endothelial1. Vascular celldysfunction (EC) injury, in defectivesystemic angiogenesis,sclerosis (SSc). endothelial-to-mesenchymal In SSc, the vascular dysfunction transition is caused (EndoMT),by vascular and coagulation and endothelial abnormalities, cell (EC) andinjury, is associateddefective angiogenesis, with abnormalities endothelial-to-mesenchymal in the immune systemtransition and extracellular (EndoMT), matrix and (ECM)coagulation metabolism. abnormalities, These abnormalities and is associated mayinduce with abnormalities myofibroblast in the differentiation,immune ECMsystem deposition, and extracellular and the development matrix (ECM) of fibrosis.metabolism. These abnormalities may induce myofibroblast differentiation, ECM deposition, and the development of fibrosis. The fibrinolytic system dissolves fibrin and maintains vascular homeostasis. The regulators of fibrinolysisThe contain fibrinolytic plasminogen system (Plg)dissolves a proenzyme, fibrin and which maintains is converted vascular to homeostasis. the active serine The protease regulators of plasmin,fibrinolysis a main component contain plasminogen of the fibrinolytic (Plg) a system,proenzyme, through which the is action converted of a tissue-type to the active plasminogen serine protease activatorplasmin, (tPA) ora urokinase-typemain component plasminogen of the fibrinolytic activator (uPA)system, and through uPA receptor the (uPAR).action of In contrast,a tissue-type alpha2-antiplasminplasminogen activator (α2AP) functions(tPA) or asurokinase-type the main inhibitor plasminogen of plasmin, activator resulting (uPA) in theand formation uPA receptor of the(uPAR). stable inactiveIn contrast, complex alpha2-antiplasmin plasmin-α2AP (α and2AP) the functions inhibition as the of fibrinolysismain inhibitor [13 ].of Plasminogenplasmin, resulting activatorin the inhibitor-1 formation (PAI-1) of the stable binds inactive and blocks complex tPA andplasmin- uPAα and2AP inhibits and the the inhibition conversion of fibrinol of Plgysis to [13]. plasminPlasminogen [14]. In addition, activator angiostatininhibitor-1 (PAI-1) is a circulating binds and inhibitor blocks tPA of angiogenesisand uPA and generatedinhibits the by conversion the proteolyticof Plg cleavageto plasmin of Plg.[14]. TheseIn addition, fibrinolytic angiostatin regulators is a havecirculating various inhibitor functions, of angiogenesis such as growth generated factor by and matrixthe proteolytic metalloproteinase cleavage of (MMP) Plg. These activation, fibrinolytic ECM regulators degradation, have and various fibrinolysis functions, (Figure such2). as It isgrowth reportedfactor that and ECs matrix synthesize metalloproteinase tPA, uPA, uPAR,(MMP) and activation, PAI-1, andECM that degradation, fibrinolytic and regulators fibrinolysis play (Figure an 2). importantIt is reported role in the that maintenance ECs synthesize of endothelial tPA, uPA, homeostasisuPAR, and PAI-1, [15–20 and]. The that levels fibrinolytic of plasmin- regulatorsα2AP play complexan important and D-dimer role inin plasmathe maintenance are elevated of endothelial in SSc [21– homeostasis23] and the expression [15–20]. The of levelsα2AP of is plasmin- elevatedα2AP in fibroticcomplex tissue and of D-dimer SSc model in miceplasma and are dermal elevated fibroblasts in SSc [21–23] obtained and from the expression patients with of α SSc2AP [24 is, 25elevated]. α2APin deficiency fibrotic tissue attenuates of SSc the model development mice and of dermal fibrosis fibroblasts in SSc model obtained mice [26 from,27] andpatients uPAR with deficiency SSc [24,25]. promotesα2AP the deficiency development attenuates of fibrosis the [development28]. In addition, of fibrosis the levels in ofSSc uPA, model soluble mice uPAR [26,27] (suPAR), and uPAR tPA, PAI-1,deficiency and angiostatinpromotes the are development elevated in SScof fibrosis [29–32]. [28]. Furthermore, In addition, uPAR-deficient the levels of uPA, mice soluble develop uPAR vasculopathy(suPAR), [ 8tPA,]. α 2APPAI-1, induces and angiosta vasculartin injury, are elevated and α2AP in SSc deficiency [29–32]. attenuatesFurthermore, the uPAR-deficient SSc-associated mice develop vasculopathy [8]. α2AP induces vascular injury, and α2AP deficiency attenuates the SSc- Int. J. Mol. Sci. 2019, 20, 619 3 of 19 Int. J. Mol. Sci. 2019, 20, x 3 of 18 vascular dysfunction in SSc model mice [33]. These fibrinolytic regulators may be associated with the SSc-associatedassociated vascular vascular dysfunction disorders. in SSc model mice [33]. These fibrinolytic
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