The uPA/uPAR System in Fibrosis Progression: Comparison
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Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Yosuke Kanno.

Urokinase plasminogen activator (uPA) is a single-chain serine protease that can cleave and activate Plg into plasmin by binding to urokinase plasminogen activator receptor (uPAR). uPA is secreted as a single-chain glycosylated zymogen called pro-uPA, and pro-uPA is activated by several proteinases, such as kallikrein, stromelysin, and plasmin. uPAR is a glycosyl-phosphatidyl-inositol anchored (GPI) membrane protein that consists of three domains: D1 (residues 1–92), D2 (residues 93–191) and D3 (residues 192–283) [50].  uPAR is cleaved between the D1 and D2 domains (linker region) and the GPI-anchor domain by several proteases, such as uPA, plasmin, MMPs, and GPI-specific phospholipase D, and then forms soluble uPAR (suPAR; full length D1-D3, D2D3, and D1).

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  • uPAR
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1. The Urokinase Plasminogen Activator (uPA) and uPAR System

The uPA and uPAR system can convert Plg into plasmin or activate intercellular signaling and regulates fibrinolysis, cell proliferation, migration, differentiation, and adhesion. The uPA/uPAR system is associated with the immune response, angiogenesis, inflammation, tissue remodeling, bone metabolism, glucose metabolism, and fibrosis progression [13,36,37,40,41,42,43,44][1][2][3][4][5][6][7][8].

1.1. uPA

uPA is a single-chain serine protease that can cleave and activate Plg into plasmin by binding to uPAR [45][9]. uPA is secreted as a single-chain glycosylated zymogen called pro-uPA, and pro-uPA is activated by several proteinases, such as kallikrein, stromelysin, and plasmin [45][9]. uPA consists of three domains: an N-terminal epidermal growth factor (EGF)-like domain (which together with the N-terminal domain form the amino-terminal fragment [ATF]), and catalytic serine protease domain [46,47][10][11]. uPA is expressed in many types of cells, including leukocytes, macrophages, tumor cells, and fibroblasts [40][4]. uPA can bind to the uPAR D1 domain through its EGF-like domain [47][11]. The uPA/uPAR interaction mediates various signal pathways, such as phosphatidylinositol 3-kinase (PI3K)/Akt, AMP-activated protein kinase (AMPK), extracellular-signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK) [27,34,48][12][13][14]. PAI-1 blocks uPA and inhibits plasmin production and the fibrinolytic system [49][15].

1.2. uPAR

uPAR is a glycosyl-phosphatidyl-inositol anchored (GPI) membrane protein that consists of three domains: D1 (residues 1–92), D2 (residues 93–191) and D3 (residues 192–283) [50][16]. uPAR is cleaved between the D1 and D2 domains (linker region) and the GPI-anchor domain by several proteases, such as uPA, plasmin, MMPs, and GPI-specific phospholipase D, and then forms soluble uPAR (suPAR; full length D1-D3, D2D3, and D1) (Figure 31) [51][17]. uPAR can interact with various transmembrane receptors, including integrins, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptors (PDGFR), vascular endothelial growth factor receptor 2 (VEGFR2), and insulin-like growth factor 1 receptor (IGF1R), as well as regulate signal transduction [32,50][16][18]. In addition, uPAR can interact with low-density lipoprotein receptor (LRP), and this uPAR/LRP interaction is associated with uPAR recycling [52][19]. uPAR can also bind to vitronectin, and the vitronectin/uPA/suPAR complex leads to increased PA activity [53][20]. Furthermore, suPAR can activate formyl peptide receptor (FPR) [54][21]. The functions of uPAR regulate various signaling pathways, such as PI3K/Akt, focal adhesion kinase (FAK), and Janus kinase (JAK)-signal transducer and activator of transcription protein (STAT), and is associated with the immune response, angiogenesis, inflammation, and fibrosis (Figure 41). uPAR is expressed on a variety of cells, including fibroblasts, monocytes, macrophages, keratinocytes, neurons, ECs and smooth muscle cells [27][12], and uPAR expression is induced by inflammation [33,55][22][23]. It has been reported that increased uPAR expression is observed in many fibrosis-related diseases, including cardiac fibrosis, idiopathic pulmonary fibrosis, and SSc (Figure 53) [56,57,58,59,60,61,62,63][24][25][26][27][28][29][30][31].
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Figure 31. The structure of uPAR.
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Figure 42. The multiple functions of uPAR.
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Figure 53. uPAR expression in fibrosis-related diseases [56,57,58,59,60,61,62,63].
uPAR expression in fibrosis-related diseases [24][25][26][27][28][29][30][31].

2. The Role of the uPA/uPAR System in Fibrosis

Fibrosis is characterized by ECM deposition due to the overproduction of ECM and the inhibition of ECM degradation. Many fibrotic events, such as vascular endothelial dysfunction and immune abnormalities, are associated with the activation and differentiation of myofibroblasts and the inhibition of ECM-depredating proteases, including MMPs and plasmin, which cause ECM deposition [9,11,64,65,66,67][32][33][34][35][36][37].
Induction of uPA activity attenuates pulmonary fibrosis in fibrosis model mice [67][37]. In addition, transplantation of uPA gene attenuates liver fibrosis in liver fibrosis model rats [68][38]. uPAR deficiency induces perivascular fibrosis, dermal fibrosis, and pulmonary fibrosis in mice [13,69,70][1][39][40] and accelerates renal fibrosis in obstructive nephropathy model mice [71][41]. In contrast, suPAR is elevated in focal segmental glomerulosclerosis (FSGS) [72][42], and uPAR deficiency attenuates LPS-induced glomerulosclerosis [73][43]. uPAR isoform 2 transgenic mice exhibit glomerulosclerosis and kidney dysfunction [74][44]. In addition, UPARANT (Ac-L-Arg-Aib-L-Arg-D-Cα(Me)Phe-NH2), which blocks uPAR binding to the FPR, restores STZ-induced renal fibrosis [75][45]; therefore, uPAR affects renal fibrosis progression.
Plasmin not only degrades fibrin but also induces MMP and PAR activity. Fibrin and PAR activation promotes fibrosis, and MMPs play an important role in ECM degradation [76,77][46][47]. In addition, plasmin-induced hepatocyte growth factor (HGF) activation and vascular endothelial growth factor (VEGF) release may affect fibrosis progression [78,79][48][49]. Furthermore, α2AP and PAI-1 deficiency attenuated fibrosis progression in fibrosis model mice [21,78,80,81,82][48][50][51][52][53]. These data suggest that the uPA/uPAR system plays a pivotal role in the progression of fibrosis through multiple plasmin-dependent and plasmin-independent mechanisms.

2.1. Myofibroblasts in Fibrosis

Myofibroblasts contribute to excessive ECM production and play a pivotal role in fibrotic disorders [3,66][36][54]. It has been reported that various cell types, including fibroblasts, pericytes, bone-marrow-derived fibrocytes, tissue-derived MSCs, ECs, epithelial cells, and macrophages give rise to myofibroblasts [83][55]. Inflammation or mechanical stresses induce pro-fibrotic factors, including transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), and interleukins (ILs). Myofibroblasts are raised from MSCs, pericytes and pre-adipocytes, epithelial cells, ECs, and macrophages through differentiation, EMT, EndoMT, or MMT induced by pro-fibrotic factors [3,5,84,85,86,87,88,89][54][56][57][58][59][60][61][62]. Furthermore, the apoptosis resistance of myofibroblasts has been observed in several fibrotic tissues [66][36]. TGF-β and PDGF inhibit myofibroblast apoptosis [66,90,91][36][63][64]. In contrast, HGF induces myofibroblast apoptosis through FAK-ERK signaling, and suppresses fibrosis progression [92,93][65][66]. The evasion of apoptosis in myofibroblasts may play a pivotal role in the progression of fibrosis.

2.1.1. The uPA/uPAR System and Myofibroblasts

Plasmin induces myofibroblast differentiation through glycogen synthase kinase-3β (GSK-3β) signaling [94][67]. In contrast, plasmin induces apoptosis of myofibroblasts [95][68]. Plasmin plays an important role in myofibroblast deposition in fibrosis. uPA overexpression attenuates myofibroblast differentiation in SSc fibroblasts [96][69], and uPA deficiency enhances myofibroblast differentiation through Endo180 and uPAR [97][70]. Furthermore, the induction of uPA activity in mice increases myofibroblast apoptosis [67][37]. In contrast, treatment with uPA increases myofibroblast differentiation [98][71], and the knockdown and inhibition of uPA attenuate TGF-β-induced myofibroblast differentiation [99][72]. uPAR deficiency in mice also increases myofibroblasts [13][1], and the blockade of uPAR cleavage by protease inhibitors prevents myofibroblast differentiation [100][73]. uPAR deficiency and silencing cause EndoMT and EMT [101,102][74][75]. In contrast, uPAR silencing by siRNA attenuates EGF-, TGF-β-, the cigarette smoke extract (CSE)-, and hypoxia-induced EMT [103,104,105,106][76][77][78][79]. The uPA/uPAR system regulates myofibroblast differentiation through multiple plasmin-dependent and plasmin-independent mechanisms.

2.1.2. uPAR-Binding Protein and Myofibroblasts

uPAR can interact with several factors, including integrins, EGFR, PDGFR, VEGFR2, caveolin-1, and LRP [50][16].
The blockade of integrin αvβ3 by RGD peptide and the knockdown of integrin αv and β1 inhibits myofibroblast differentiation [107,108][80][81]. In addition, RGD peptide reverts EndoMT [109][82], and integrin α3 knockout prevents TGF-β-induced EMT [110][83]. In contrast, integrin α5 silencing promotes myofibroblast differentiation [111][84]. EGFR activation promotes an increase in myofibroblasts [112][85]. EGF neutralization inhibits myofibroblast proliferation [113][86], and the inhibition of EGFR signaling blocks EMT and EndoMT [114,115][87][88]. The inhibition of PDGFR promotes a reduction in myofibroblasts [116][89] and interferes with EMT [117][90]. In addition, neutralization of TGF-β and PDGFR signaling abolishes platelet-induced EndoMT [118][91]. VEGF-VEGFR2 signaling promotes EMT [119][92], and VEGFR2 inhibitor reverses TGF-β-induced EMT [120][93]. In contrast, VEGFR2 antagonism induces EndoMT [121][94]. The downregulation of caveolin is associated with anti-apoptotic properties of myofibroblasts [122][95]. Overexpression of caveolin-1 inhibits EMT [123][96], and the disappearance of caveolin-1 causes EMT and EndoMT [124,125][97][98]. The loss of LRP-1 promotes myofibroblast differentiation [126][99].
These uPAR-associated factors regulate the activation and differentiation of myofibroblasts, suggesting that the interaction with uPAR may play an important role in myofibroblast differentiation.

2.1.3. Other Fibrinolytic Factors and Myofibroblasts

The uPA/uPAR system, as well as other fibrinolytic factors, such as tPA, PAI-1 and α2AP are associated with myofibroblast activation and differentiation.
tPA is a Plg activator that also converts Plg into plasmin. tPA deficiency increases apoptosis of interstitial myofibroblasts in a mouse model of obstructive injury, and tPA is associated with myofibroblast apoptosis [127][100]. In addition, tPA induces myofibroblast activation through LRP-1 activation [128][101].
PAI-1 regulates plasmin production by inhibiting tPA and uPA. PAI-1-specific inhibitor attenuates TGF-β-mediated myofibroblast differentiation and EMT [129][102]. The knockdown of PAI-1 by siRNA and PAI-1 inhibition decreases myofibroblasts [130,131][103][104]. TGF-β is known to induce PAI-1 expression and inhibit uPA, and uPA binding to PAI-1 induces myofibroblast differentiation [98][71]. Increases in the PAI-1 expression may promote fibrosis progression. However, it has been reported that PAI-1 deficiency increases myofibroblasts, and PAI-1 deficient ECs are more susceptible to TGF-β-induced EndoMT than wild-type ECs [132,133,134][105][106][107]. Elevated PAI-1 expression reportedly decreases myofibroblasts [135][108].
α2AP rapidly inactivates plasmin by inducing the formation of plasmin–α2AP complex. In contrast, α2AP deficiency attenuates dermal fibrosis in mice [80][51]. In addition, α2AP promotes myofibroblast differentiation and fibrosis through ATGL activation [136][109], and the blockade of α2AP by neutralizing antibodies or miRNA attenuates myofibroblast differentiation and fibrosis [22,137][110][111]. Furthermore, α2AP is associated with the induction of EMT and EndoMT [21,138][50][112]. α2AP may also regulate myofibroblast activation and differentiation through multiple functions.

2.2. Suppression of ECM Depredating Protease in Fibrosis

The suppression of ECM degradation, as well as the overproduction of ECM, causes the progression of fibrosis [10][113]. Proteases, including MMPs, plasmin, and uPA, regulate ECM degradation, and the activity of these proteases is inhibited by TIMPs, α2AP, and PAI-1, respectively. An imbalance between proteases and anti-proteases may promote fibrosis progression.
MMPs can be divided into six classes: collagenases, including MMP-1, MMP-8, and MMP-13; gelatinases, including MMP-2 and MMP-9; stromelysins, including MMP-3, MMP-10, and MMP-11; matrilysins, including MMP-7 and MMP-26; membrane-type MMPs, including MMP-14, MMP-15, MMP-16, MMP-17, MMP-24, and MMP-25; and others [139][114]. MMPs degrade ECM components, including collagen, fibronectin, laminin, entactin, tenascin, thrombospondin, and perlecan, and maintain ECM homeostasis. MMP-3 induces inactivation of α2AP and PAI-1 [19,140][115][116]. Several proteinases, including plasmin and uPA, induce the activation of MMPs. Plasmin activates MMP-1, MMP-3, MMP-9, MMP-10, and MMP-13, and uPA activates MMP-2 and MMP-9 in a plasmin-independent manner [140][116]. In contrast, uPAR deficiency attenuates MMP-2 and MMP-9 expression and activation [13][1]. Thus, the uPA/uPAR system affects MMP expression and activation.
TIMPs (TIMP-1-4) are important inhibitors of MMPs [18][117]. TIMPs are secreted by various cells, including immune cells, fibroblasts, and hepatocytes, and tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) induce TIMP expression [10,18,141,142][113][117][118][119]. TIMP-1 and TIMP-2 levels are elevated in several types of fibrosis, including SSc, pulmonary fibrosis, liver cirrhosis, renal fibrosis, and myocardial fibrosis [14,18,65,143,144,145,146,147,148,149,150][35][117][120][121][122][123][124][125][126][127][128]. α2AP is elevated in fibrotic tissue, including skin and renal fibrosis [21,22,151][50][110][129]. Several fibrosis-associated factors, such as connective tissue growth factor (CTGF), high mobility group box 1 (HMGB1), and interferon-γ (IFN-γ) induce α2AP production [20,23,151][129][130][131]. The overexpression of PAI-1 attenuates ECM degradation by inhibiting the Plg activation system [152][132]. PAI-1 is regulated by various cytokines, such as TGF-β, EGF, and IL-1β [133][106]. PAI-1 expression is elevated in various types of fibrosis, including skin fibrosis, lung fibrosis, and renal fibrosis [133,153,154][106][133][134]. Increases in the expression of these factors may contribute to fibrosis progression by suppressing ECM degradation.

3. Vascular Endothelial Dysfunction in Fibrosis

Vascular endothelial dysfunction is caused by EC injury, apoptosis, defective angiogenesis and vasculogenesis, EndoMT, and excessive coagulation, leading to perivascular inflammation, tissue hypoxia, oxidative stress induction, myofibroblast accumulation, hypertension, fibrin deposition, and PARs activation [155,156,157][135][136][137].

3.1. The Role of the uPA/uPAR System in EC Functions

Plasmin is known to play an important role on the maintenance of the vascular endothelial function through fibrinolysis, MMP and cytokine activation, and ECM degradation [11,158][33][138]. In addition, plasmin regulates fibrin-, MMP-, and cytokine-mediated EC proliferation, migration, and apoptosis [159,160,161][139][140][141]. In contrast, uPA protects ECs from apoptosis [162[142][143],163], and promotes EC proliferation [164][144]. The proteolytically inactive recombinant of uPA inhibits EC migration [165][145], and uPAR deficiency alters EC functions, including adhesion, migration, proliferation, and capillary tube formation, and decreases angiogenic functions [166][146]. uPAR antagonist inhibits the motility of ECs [167][147]. In addition, the uPA/uPAR system cross-talks with integrins and VEGFR2 and mediates EC tube formation [168][148]. Furthermore, uPAR-integrin interaction regulates EC migration [169][149], and the uPA/uPAR system is associated with growth factor-induced EC migration [170,171][150][151]. The uPA/uPAR system may regulate EC functions through plasmin-dependent or plasmin-independent mechanisms.

3.2. The Role of the uPA/uPAR System in Angiogenesis

uPA regulates plasmin production and plays an important role in angiogenesis [27][12]. PA regulates the VEGFR1 and VEGFR2 expression by binding to haematopoietically expressed homeobox protein (HHEX) transcription factor and mediates angiogenesis [172][152]. uPA and uPAR shRNA enhance TIMP-1-mediated soluble VEGFR1 (sVEGFR1) secretion, and inhibit angiogenesis [173][153]. Plasmin regulates the vascular endothelial function through fibrinolysis, ECM degradation, and activation of growth factors [11][33]. In addition, plasmin can release pro-angiogenic factor VEGF from ECM and plays an important role in angiogenesis [174][154]. The deficiency of α2AP promotes angiogenesis through VEGF over-release in the wound-healing process [79][49], and α2AP causes the impairment of VEGF signaling [175][155].
Interaction of uPAR with VEGFR2 regulates VEGF signaling and promotes angiogenesis. [176][156]. Domain 2 of uPAR regulates uPA-mediated angiogenesis through integrin β1 and VEGFR2 [177][157]. uPAR also regulates factor XII-stimulated angiogenesis through integrin β1 and EGFR [178][158]. MMP-12 can cleave uPAR and cause the impairment of angiogenesis [179][159]. The interaction of uPAR with various factors may regulate its intracellular signaling and play an important role in angiogenesis. In contrast, suPAR and its ser-arg-ser-arg-tyr (SRSRY) sequence (uPAR88-92 sequence) induces angiogenesis [180][160]. uPAR may thus regulate angiogenesis through multiple mechanisms.

3.3. The Role of the uPA/uPAR System in Coagulation

Hypercoagulation involving fibrin formation contributes to fibrosis progression [77][47]. The uPA/uPAR system plays a pivotal role in fibrin degradation through plasmin production. uPA and plasmin inhibitors, PAI-1 and α2AP, are elevated in several fibrotic tissue types [11][33], and the increase in the expression of these factors may cause the impairment of fibrinolysis through the direct inhibition of uPA and plasmin. The impairment of fibrinolysis causes fibrosis, and improvement in fibrinolysis restores fibrosis [77][47]. In addition, fibrin degradation product fragment can potentiate TGF-β-induced myofibroblast formation [181][161]. An imbalance in coagulation and fibrinolysis may thus play a critical role in fibrosis progression.

3.4. The Role of the uPA/uPAR System in Vascular Tone Alteration and Hypertension

Hypertension causes cardiac fibrosis [182][162], while fibrosis leads to pulmonary hypertension [183][163]. The balance between vasoconstrictor and vasodilator mediators, such as nitric oxide (NO), prostacyclin (PGI2), and endothelin-1 (ET-1), regulates vascular tone, and a shift toward vasoconstriction is associated with hypertension progression [184][164]. The ratio of uPA and PAI-1 is decreased in idiopathic pulmonary fibrosis patients with pulmonary hypertension [185][165]. uPA deficiency attenuates hypoxia-induced pulmonary arterial hypertension (PAH) progression [186][166]. uPAR is associated with SSc-associated PAH [187][167]. NO is a major vasodilation mediator, and is produced by NO synthase (NOS, including endothelial NOS [eNOS] and inducible NOS [iNOS]). uPA induces eNOS activation through LRP [188][168]. Treatment with UPARANT, which inhibits uPAR binding to the FPR, attenuates iNOS and NO production [189][169]. In contrast, iNOS and NO downregulate uPAR expression under hypoxic conditions [190][170]. The uPA/uPAR system may be associated with vasodilation and the onset of hypertension.

4. Immune Abnormalities and Inflammation in Fibrosis

Chronic inflammation leads to excessive tissue repair and triggers fibrosis progression [191][171]. Various stimuli, such as tissue injury, allergic response, autoimmune conditions, and infection, can cause inflammation and recruit and activate immune cells [192][172]. Immune cells, including T-cells, B-cells, macrophages, and dendritic cells (DCs), have been observed in fibrotic tissues [191,193][171][173]. T-cells (Th1 cells, Th2 cells, Th17 cells, and regulatory T-cells) secrete various cytokines, including IFN-γ, IL-4, IL-6, IL-12, IL-13, IL-17, and IL-22, and regulate B-cell and macrophage activation, macrophage polarization, myofibroblast differentiation, and ECM production [191,194][171][174]. B-cells induce autoantibody and cytokine production and affect EC apoptosis and ECM production [191,195][171][175]. In addition, B-cell depletion via antibodies against CD20 attenuates fibrosis progression through the suppression of M2 macrophage polarization in mice [196][176]. Macrophages play a pivotal role in fibrosis progression, and macrophage depletion markedly suppresses fibrosis progression [151][129]. Macrophages are divided into M1 and M2 macrophages subsets, and M2 macrophages are elevated under conditions of fibrotic disease [197,198][177][178]. M2 macrophage polarization is induced by IL-4 and IL-13 [199][179], and the inhibition of IL-4 and IL-13 signaling by IL-4Rα antibodies suppresses fibrosis progression in mice [151][129]. The increase in these immune cells induces production of various pro-fibrotic factors and regulates the inflammatory response, vascular homeostasis, myofibroblast differentiation, and ECM production. Abnormality of the innate and adaptive immune system is associated with fibrosis progression.

5. The Role of the uPA/uPAR System in Inflammation and the Immune System

The uPA/uPAR system regulates cell recruitment, migration, and adhesion, and supports the innate and adaptive immune systems through proteolytic and non-proteolytic mechanisms [200][180]. Plasmin induced by the uPA/uPAR system has both pro- and anti-inflammatory effects and regulates chemotaxis, invasion, phagocytosis, and cytokine production through PAR-1 or Annexin A2 in various cell types, including monocytes, macrophages, and DCs [201,202,203][181][182][183]. In addition, Plg/plasmin regulates macrophage activation, polarization and efferocytosis [204,205][184][185]. Furthermore, plasmin can activate complement factors (C3 and C5), factor XII, and MMPs [203][183]. Plasmin is also associated with the polarization of T cells [206][186], and mediates the innate and adaptive immune systems.
uPA regulates macrophage chemotaxis, neutrophil activation, and migration through uPAR-dependent or uPAR-independent mechanisms [207][187]. uPA also mediates the inflammatory response, such as inflammatory cytokine production and suppression of the NF-κB pathway through plasmin activation [34,200][13][180]. Furthermore, uPA induces the production of M2 phenotype macrophages [208][188]. In contrast, uPAR interacts with several receptors, including integrins and LRP, and participates in the initiation of the innate immune response through the induction of cell adhesion and migration [200][180]. In addition, uPAR regulates toll-like receptor (TLR) 2, 4, and 7 signaling, and affects inflammation (cytokine production, mediation of NF-κB pathway) and immune responses (neutrophil and macrophage activation, macrophage efferocytosis) [38,209,210,211][189][190][191][192]. The expression and release of suPAR is induced by inflammation and immune activation [212][193]. The uPAR-derived ser-arg-ser-arg-tyr (SRSRY) peptide (uPAR88-92 sequence) can interact with FPR1 and is associated with chemokine regulation and monocyte migration [212,213][193][194]. The uPA/uPAR system also affects T-cell priming and T-cell effector function [200][180].
This system has multiple functions and contributes to the inflammatory response and innate and adaptive immune responses.

References

  1. Kanno, Y.; Kaneiwa, A.; Minamida, M.; Kanno, M.; Tomogane, K.; Takeuchi, K.; Okada, K.; Ueshima, S.; Matsuo, O.; Matsuno, H. The Absence of uPAR Is Associated with the Progression of Dermal Fibrosis. J. Investig. Dermatol. 2008, 128, 2792–2797.
  2. Kanno, Y.; Matsuno, H.; Kawashita, E.; Okada, K.; Suga, H.; Ueshima, S.; Matsuo, O. Urokinase-type plasminogen activator receptor is associated with the development of adipose tissue. Thromb. Haemost. 2010, 104, 1124–1132.
  3. Del Rosso, M.; Margheri, F.; Serratì, S.; Chillà, A.; Laurenzana, A.; Fibbi, G. The urokinase receptor system, a key regulator at the intersection between inflammation, immunity, and coagulation. Curr. Pharm. Des. 2011, 17, 1924–1943.
  4. Napolitano, F.; Montuori, N. The Role of the Plasminogen Activation System in Angioedema: Novel Insights on the Patho-genesis. J. Clin. Med. 2021, 10, 518.
  5. Mahmood, N.; Mihalcioiu, C.; Rabbani, S.A. Multifaceted Role of the Urokinase-Type Plasminogen Activator (uPA) and Its Receptor (uPAR): Diagnostic, Prognostic, and Therapeutic Applications. Front. Oncol. 2018, 8, 24.
  6. Navaratna, D.; Menicucci, G.; Maestas, J.; Srinivasan, R.; McGuire, P.; Das, A. A peptide inhibitor of the urokinase/urokinase receptor system inhibits alteration of the blood-retinal barrier in diabetes. FASEB J. 2008, 22, 3310–3317.
  7. Kalbasi, A.P.; Patecki, M.; Tkachuk, S.; Kiyan, Y.; Haller, H.; Dumler, I. Urokinase receptor mediates osteoclastogenesis via M-CSF release from osteoblasts and the c-Fms/PI3K/Akt/NF-κB pathway in osteoclasts. J. Bone Miner. Res. 2015, 30, 379–388.
  8. Tomogane, K.; Kanno, Y.; Kawashita, E.; Okada, K.; Takeuchi, K.; Ueshima, S.; Matsuo, O.; Matsuno, H. The Absence of Urokinase-type Plasminogen Activator Receptor Plays a Role in the Insulin-independent Glucose Metabolism. J. Cardiovasc. Pharmacol. 2011, 57, 334–339.
  9. Masucci, M.T.; Minopoli, M.; Di Carluccio, G.; Motti, M.L.; Carriero, M.V. Therapeutic Strategies Targeting Urokinase and Its Receptor in Cancer. Cancers 2022, 14, 498.
  10. Yepes, M.; Woo, Y.; Martin-Jimenez, C. Plasminogen Activators in Neurovascular and Neurodegenerative Disorders. Int. J. Mol. Sci. 2021, 22, 4380.
  11. Kumar, A.A.; Buckley, B.J.; Ranson, M. The Urokinase Plasminogen Activation System in Pancreatic Cancer: Prospective Diagnostic and Therapeutic Targets. Biomolecules 2022, 12, 152.
  12. Ismail, A.; Shaker, B.; Bajou, K. The Plasminogen-Activator Plasmin System in Physiological and Pathophysiological Angio-genesis. Int. J. Mol. Sci. 2021, 23, 337.
  13. Kanno, Y.; Ishisaki, A.; Kawashita, E.; Kuretake, H.; Ikeda, K.; Matsuo, O. uPA Attenuated LPS-induced Inflammatory Osteoclas-togenesis through the Plasmin/PAR-1/Ca2+/CaMKK/AMPK Axis. Int. J. Biol. Sci. 2016, 12, 63–71.
  14. Dinesh, P.; Rasool, M. uPA/uPAR signaling in rheumatoid arthritis: Shedding light on its mechanism of action. Pharmacol. Res. 2018, 134, 31–39.
  15. Vaughan, D.E.; Rai, R.; Khan, S.S.; Eren, M.; Ghosh, A.K. Plasminogen Activator Inhibitor-1 Is a Marker and a Mediator of Senescence. Arter. Thromb. Vasc. Biol. 2017, 37, 1446–1452.
  16. Alfano, D.; Franco, P.; Stoppelli, M.P. Modulation of Cellular Function by the Urokinase Receptor Signalling: A Mechanistic View. Front. Cell Dev. Biol. 2022, 10, 818616.
  17. Enocsson, H.; Sjöwall, C.; Wetterö, J. Soluble urokinase plasminogen activator receptor--a valuable biomarker in systemic lupus erythematosus? Clin. Chim. Acta 2015, 444, 234–241.
  18. Blasi, F.; Carmeliet, P. uPAR: A versatile signalling orchestrator. Nat. Rev. Mol. Cell Biol. 2002, 3, 932–943.
  19. Czekay, R.-P.; Kuemmel, T.A.; Orlando, R.A.; Farquhar, M.G. 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.
  20. Chavakis, T.; Kanse, S.M.; Yutzy, B.; Lijnen, H.R.; Preissner, K.T. Vitronectin concentrates proteolytic activity on the cell surface and extracellular matrix by trapping soluble urokinase receptor-urokinase complexes. Blood 1998, 91, 2305–2312.
  21. Selleri, C.; Montuori, N.; Ricci, P.; Visconte, V.; Carriero, M.V.; Sidenius, N.; Serio, B.; Blasi, F.; Rotoli, B.; Rossi, G. Involvement of the urokinase-type plasminogen activator receptor in hematopoietic stem cell mobilization. Blood 2005, 105, 2198–2205.
  22. Smith, H.W.; Marshall, C.J. Regulation of cell signalling by uPAR. Nat. Rev. Mol. Cell Biol. 2010, 11, 23–36.
  23. Li Santi, A.; Napolitano, F.; Montuori, N.; Ragno, P. The Urokinase Receptor: A Multifunctional Receptor in Cancer Cell Biology. Therapeutic Implications. Int. J. Mol. Sci. 2021, 22, 22084111.
  24. Saxena, A.; Izmirly, P.M.; Han, S.W.; Briassouli, P.; Rivera, T.L.; Zhong, H.; Friedman, D.M.; Clancy, R.M.; Buyon, J.P. Serum Biomarkers of Inflammation, Fibrosis, and Cardiac Function in Facilitating Diagnosis, Prognosis, and Treatment of Anti-SSA/Ro-Associated Cardiac Neonatal Lupus. J. Am. Coll. Cardiol. 2015, 66, 930–939.
  25. Akdoğan, J.P.; Yücel, A.A.; Sargin, Z.G.; Sönmez, C.; Yilmaz, G.E.; Özenirler, S. Evaluation of Plasma Urokinase-Type Plasminogen Activator Receptor (UPAR) in Patients with Chronic Hepatitis B, C and Non-Alcoholic Fatty Liver Disease (NAFLD) as Serological Fibrosis Marker. J. Clin. Exp. Hepatol. 2019, 9, 29–33.
  26. Zimmermann, H.W.; Koch, A.; Seidler, S.; Trautwein, C.; Tacke, F. Circulating soluble urokinase plasminogen activator is elevated in patients with chronic liver disease, discriminates stage and aetiology of cirrhosis and predicts prognosis. Liver Int. 2012, 32, 500–509.
  27. Xiao, W.; Hsu, Y.-P.; Ishizaka, A.; Kirikae, T.; Moss, R.B. Sputum Cathelicidin, Urokinase Plasminogen Activation System Components, and Cytokines Discriminate Cystic Fibrosis, COPD, and Asthma Inflammation. Chest 2005, 128, 2316–2326.
  28. Desai, B.; Mattson, J.; Paintal, H.; Nathan, M.; Shen, F.; Beaumont, M.; Malinao, M.C.; Li, Y.; Canfield, J.; Basham, B. Differential expression of monocyte/macrophage-selective markers in human idiopathic pulmonary fibrosis. Exp. Lung Res. 2011, 37, 227–238.
  29. Chebotareva, N.; Vinogradov, A.; Cao, V.; Gindis, A.; Berns, A.; Alentov, I.; Sergeeva, N. Serum levels of plasminogen activator urokinase receptor and cardiotrophin-like cytokine factor 1 in patients with nephrotic syndrome. Clin. Nephrol. 2022, 97, 103–110.
  30. Trimarchi, H.; Canzonieri, R.; Schiel, A.; Costales-Collaguazo, C.; Stern, A.; Paulero, M.; Rengel, T.; Andrews, J.; Iotti, A.; Forrester, M. In IgA Nephropathy, Glomerulo-sclerosis Is Associated with Increased Urinary CD80 Excretion and Urokinase-Type Plasminogen Activator Receptor-Positive Podocyturia. Nephron Extra 2017, 7, 52–61.
  31. Legány, N.; Toldi, G.; Distler, J.H.; Beyer, C.; Szalay, B.; Kovács, L.; Vásárhelyi, B.; Balog, A. Increased plasma soluble urokinase plasminogen activator receptor levels in systemic sclerosis: Possible association with microvascular abnormalities and extent of fibrosis. Clin. Chem. Lab. Med. 2015, 53, 1799–1805.
  32. Egea-Zorrilla, A.; Vera, L.; Saez, B.; Pardo-Saganta, A. Promises and Challenges of Cell-Based Therapies to Promote Lung Re-generation in Idiopathic Pulmonary Fibrosis. Cells 2022, 11, 2595.
  33. Kanno, Y. The Role of Fibrinolytic Regulators in Vascular Dysfunction of Systemic Sclerosis. Int. J. Mol. Sci. 2019, 20, 619.
  34. Gilbane, A.J.; Denton, C.P.; Holmes, A.M. Scleroderma pathogenesis: A pivotal role for fibroblasts as effector cells. Thromb. Haemost. 2013, 15, 215–219.
  35. Hasanzadeh, A.; Rafiei, A.; Kazemi, M.; Beiromvand, M.; Bahreini, A.; Khanahmad, H. The Role of Tissue Inhibitor of Metallopro-teinase-1 and 2 in Echinococcus granulosus senso lato-Induced Human Hepatic Fibrosis. Acta Parasitol. 2022, 67, 851–857.
  36. Hinz, B.; Lagares, D. Evasion of apoptosis by myofibroblasts: A hallmark of fibrotic diseases. Nat. Rev. Rheumatol. 2019, 16, 11–31.
  37. Horowitz, J.C.; Tschumperlin, D.J.; Kim, K.K.; Osterholzer, J.J.; Subbotina, N.; Ajayi, I.O.; Teitz-Tennenbaum, S.; Virk, A.; Dotson, M.; Liu, F. Urokinase Plasminogen Activator Overex-pression Reverses Established Lung Fibrosis. Thromb Haemost. 2019, 119, 1968–1980.
  38. Sun, C.; Li, D.G.; Chen, Y.W.; Chen, Y.W.; Wang, B.C.; Sun, Q.L.; Lu, H.M. Transplantation of urokinase-type plasminogen activator gene-modified bone marrow-derived liver stem cells reduces liver fibrosis in rats. J. Gene Med. 2008, 10, 855–866.
  39. Dergilev, K.; Beloglazova, I.; Tsokolaeva, Z.; Vasilets, Y.; Parfenova, E. Deficiency of Urokinase-Type Plasminogen Activator Receptor Is Associated with the Development of Perivascular Fibrosis in Mouse Heart. Bull. Exp. Biol. Med. 2022, 173, 5–9.
  40. Manetti, M.; Rosa, I.; Milia, A.F.; Guiducci, S.; Carmeliet, P.; Ibba-Manneschi, L.; Matucci-Cerinic, M. Inactivation of urokinase-type plasminogen activator receptor (uPAR) gene induces dermal and pulmonary fibrosis and peripheral microvasculopathy in mice: A new model of experimental scleroderma? Ann. Rheum. Dis. 2014, 73, 1700–1709.
  41. Zhang, G.; Kim, H.; Cai, X.; López-Guisa, J.M.; Alpers, C.E.; Liu, Y.; Carmeliet, P.; Eddy, A.A. Urokinase Receptor Deficiency Accelerates Renal Fibrosis in Obstructive Nephropathy. J. Am. Soc. Nephrol. 2003, 14, 1254–1271.
  42. Wei, C.; El Hindi, S.; Li, J.; Fornoni, A.; Goes, N.; Sageshima, J.; Maiguel, D.; Karumanchi, S.A.; Yap, H.K.; Saleem, M. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 2011, 17, 952–960.
  43. Wei, C.; Möller, C.C.; Altintas, M.M.; Li, J.; Schwarz, K.; Zacchigna, S.; Xie, L.; Henger, A.; Schmid, H.; Rastaldi, M.P. Modification of kidney barrier function by the urokinase receptor. Nat. Med. 2007, 14, 55–63.
  44. Wei, C.; Li, J.; Adair, B.D.; Zhu, K.; Cai, J.; Merchant, M.; Samelko, B.; Liao, Z.; Koh, K.H.; Tardi, N.J. uPAR isoform 2 forms a dimer and induces severe kidney disease in mice. J. Clin. Investig. 2019, 129, 1946–1959.
  45. Dal Monte, M.; Cammalleri, M.; Pecci, V.; Carmosino, M.; Procino, G.; Pini, A.; De Rosa, M.; Pavone, V.; Svelto, M.; Bagnoli, P. Inhibiting the urokinase-type plasminogen activator receptor system recovers STZ-induced diabetic nephropathy. J. Cell. Mol. Med. 2019, 23, 1034–1049.
  46. Schuliga, M.; Grainge, C.; Westall, G.; Knight, D. The fibrogenic actions of the coagulant and plasminogen activation systems in pulmonary fibrosis. Int. J. Biochem. Cell Biol. 2018, 97, 108–117.
  47. Oh, H.; Park, H.E.; Song, M.S.; Kim, H.; Baek, J.-H. The Therapeutic Potential of Anticoagulation in Organ Fibrosis. Front. Med. 2022, 9, 866746.
  48. Bauman, K.A.; Wettlaufer, S.H.; Okunishi, K.; Vannella, K.M.; Stoolman, J.S.; Huang, S.K.; Courey, A.J.; White, E.S.; Hogaboam, C.M.; Simon, R.H. The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice. J. Clin. Investig. 2010, 120, 1950–1960.
  49. Kanno, Y.; Hirade, K.; Ishisaki, A.; Nakajima, K.; Suga, H.; Into, T.; Matsushita, K.; Okada, K.; Matsuo, O.; Matsuno, H. Lack of alpha2-antiplasmin improves cutaneous wound healing via over-released vascular endothelial growth factor-induced angiogenesis in wound lesions. J. Thromb. Haemost. 2006, 4, 1602–1610.
  50. Kanno, Y.; Kawashita, E.; Kokado, A.; Kuretake, H.; Ikeda, K.; Okada, K.; Seishima, M.; Ueshima, S.; Matsuo, O.; Matsuno, H. α2AP mediated myofibroblast formation and the development of renal fibrosis in unilateral ureteral obstruction. Sci. Rep. 2014, 4, srep05967.
  51. Kanno, Y.; Kuroki, A.; Okada, K.; Tomogane, K.; Ueshima, S.; Matsuo, O.; Matsuno, H. alpha2-Antiplasmin is involved in the production of transforming growth factor beta1 and fibrosis. J. Thromb. Haemost. 2007, 5, 2266–2273.
  52. Beier, J.I.; Kaiser, J.P.; Guo, L.; Martínez-Maldonado, M.; Arteel, G.E. Plasminogen activator inhibitor-1 deficient mice are protected from angiotensin II-induced fibrosis. Arch. Biochem. Biophys. 2011, 510, 19–26.
  53. Chuang-Tsai, S.; Sisson, T.H.; Hattori, N.; Tsai, C.G.; Subbotina, N.M.; Hanson, K.E.; Simon, R.H. Reduction in Fibrotic Tissue Formation in Mice Genetically Deficient in Plasminogen Activator Inhibitor. Am. J. Pathol. 2003, 163, 445–452.
  54. Ortiz-Zapater, E.; Signes-Costa, J.; Montero, P.; Roger, I. Lung Fibrosis and Fibrosis in the Lungs: Is It All about Myofibroblasts? Biomedicines 2022, 10, 1423.
  55. Tai, Y.; Woods, E.L.; Dally, J.; Kong, D.; Steadman, R.; Moseley, R.; Midgley, A.C. Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis. Biomolecules 2021, 11, 1095.
  56. Wei, J.; Xu, Z.; Yan, X. The role of the macrophage-to-myofibroblast transition in renal fibrosis. Front. Immunol. 2022, 13, 934377.
  57. Platel, V.; Faure, S.; Corre, I.; Clere, N. Endothelial-to-Mesenchymal Transition (EndoMT): Roles in Tumorigenesis, Metastatic Extravasation and Therapy Resistance. J. Oncol. 2019, 2019, 8361945.
  58. Wang, F.; Xia, H.; Yao, S. Regulatory T cells are a double-edged sword in pulmonary fibrosis. Int. Immunopharmacol. 2020, 84, 106443.
  59. Wang, S.; Meng, X.M.; Ng, Y.Y.; Ma, F.Y.; Zhou, S.; Zhang, Y.; Yang, C.; Huang, X.R.; Xiao, J.; Wang, Y.Y. TGF-β/Smad3 signalling regulates the transition of bone marrow-derived macrophages into myofibroblasts during tissue fibrosis. Oncotarget 2015, 7, 8809–8822.
  60. Derada Troletti, C.; Fontijn, R.D.; Gowing, E.; Charabati, M.; van Het Hof, B.; Didouh, I.; van der Pol, S.M.A.; Geerts, D.; Prat, A.; van Horssen, J. Inflammation-induced endothelial to mesenchymal transition promotes brain endothelial cell dysfunction and occurs during multiple sclerosis pathophysiology. Cell Death Dis. 2019, 10, 45.
  61. Wu, N.; Wang, Y.; Wang, K.; Zhong, B.; Liao, Y.; Liang, J.; Jiang, N. Cathepsin K regulates the tumor growth and metastasis by IL-17/CTSK/EMT axis and mediates M2 macrophage polarization in castration-resistant prostate cancer. Cell Death Dis. 2022, 13, 813.
  62. Paquissi, F.; Abensur, H. The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis. Front Med. 2021, 8, 654912.
  63. Zhang, H.; Phan, S. Inhibition of myofibroblast apoptosis by transforming growth factor beta. Am. J. Respir. Cell Mol. Biol. 1999, 21, 658–665.
  64. Tang, W.W.; Ulich, T.R.; Lacey, D.L.; Hill, D.C.; Qi, M.; Kaufman, S.A.; Van, G.Y.; Tarpley, J.E.; Yee, J.S. Platelet-derived growth factor-BB induces renal tubulointerstitial myofibroblast formation and tubulointerstitial fibrosis. Am. J. Pathol. 1996, 148, 1169–1180.
  65. Iekushi, K.; Taniyama, Y.; Azuma, J.; Sanada, F.; Kusunoki, H.; Yokoi, T.; Koibuchi, N.; Okayama, K.; Rakugi, H.; Morishita, R. Hepatocyte growth factor attenuates renal fibrosis through TGF-β1 suppression by apoptosis of myofibroblasts. J. Hypertens. 2010, 28, 2454–2461.
  66. Yoshimine, H.; Tanoue, S.; Ibi, Y.; Minami, M.; Nakahara, M.; Tokunaga, K.; Kanmura, S.; Ido, A. Hepatocyte growth factor ameliorates methyl-glyoxal-induced peritoneal inflammation and fibrosis in mouse model. Clin. Exp. Nephrol. 2021, 25, 935–943.
  67. Jeffers, A.; Qin, W.; Owens, S.; Koenig, K.B.; Komatsu, S.; Giles, F.J.; Schmitt, D.M.; Idell, S.; Tucker, T.A. Glycogen Synthase Kinase-3β Inhibition with 9-ING-41 At-tenuates the Progression of Pulmonary Fibrosis. Sci. Rep. 2019, 9, 18925.
  68. Kochtebane, N.; Choqueux, C.; Passefort, S.; Nataf, P.; Messika-Zeitoun, D.; Bartagi, A.; Michel, J.B.; Anglés-Cano, E.; Jacob, M.P. Plasmin induces apoptosis of aortic valvular myofibroblasts. J. Pathol. 2009, 221, 37–48.
  69. He, Y.; Tsou, P.; Khanna, D.; Sawalha, A. Methyl-CpG-binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts. Ann. Rheum. Dis. 2018, 77, 1208–1218.
  70. Sugioka, K.; Nishida, T.; Kodama-Takahashi, A.; Murakami, J.; Mano, F.; Okada, K.; Fukuda, M.; Kusaka, S. Urokinase-type plasminogen activator negatively regulates α-smooth muscle actin expression via Endo180 and the uPA receptor in corneal fibroblasts. Am. J. Physiol. Physiol. 2022, 323, C104–C115.
  71. Wang, L.; Ly, C.M.; Ko, C.-Y.; Meyers, E.E.; Lawrence, D.A.; Bernstein, A.M. uPA Binding to PAI-1 Induces Corneal Myofibroblast Differentiation on Vitronectin. Investig. Opthalmology Vis. Sci. 2012, 53, 4765–4775.
  72. Vorstandlechner, V.; Laggner, M.; Copic, D.; Klas, K.; Direder, M.; Chen, Y.; Golabi, B.; Haslik, W.; Radtke, C.; Tschachler, E. The serine proteases dipeptidyl-peptidase 4 and urokinase are key molecules in human and mouse scar formation. Nat. Commun. 2021, 12, 6242.
  73. Bernstein, A.M.; Twining, S.S.; Warejcka, D.J.; Tall, E.; Masur, S.K. Urokinase Receptor Cleavage: A Crucial Step in Fibroblast-to-Myofibroblast Differentiation. Mol. Biol. Cell 2007, 18, 2716–2727.
  74. Manetti, M.; Romano, E.; Rosa, I.; Guiducci, S.; Bellando-Randone, S.; De Paulis, A.; Ibba-Manneschi, L.; Matucci-Cerinic, M. Endothelial-to-mesenchymal transition contributes to endothelial dysfunction and dermal fibrosis in systemic sclerosis. Ann. Rheum. Dis. 2017, 76, 924–934.
  75. Semina, E.V.; Rubina, K.A.; Shmakova, A.A.; Rysenkova, K.D.; Klimovich, P.S.; Aleksanrushkina, N.A.; Sysoeva, V.Y.; Karagyaur, M.N.; Tkachuk, V.A. Downregulation of uPAR promotes urokinase translocation into the nucleus and epithelial to mesenchymal transition in neuroblastoma. J. Cell. Physiol. 2020, 235, 6268–6286.
  76. Wang, P.; Ma, M.; Zhang, S. EGF-induced urokinase plasminogen activator receptor promotes epithelial to mesenchymal tran-sition in human gastric cancer cells. Oncol. Rep. 2017, 38, 2325–2334.
  77. Laurenzana, A.; Biagioni, A.; Bianchini, F.; Peppicelli, S.; Chillà, A.; Margheri, F.; Luciani, C.; Pimpinelli, N.; Del Rosso, M.; Calorini, L. Inhibition of uPAR-TGFβ crosstalk blocks MSC-dependent EMT in melanoma cells. J. Mol. Med. 2015, 93, 783–794.
  78. Wang, Q.; Wang, Y.; Zhang, Y.; Zhang, Y.; Xiao, W. The role of uPAR in epithelial-mesenchymal transition in small airway epi-thelium of patients with chronic obstructive pulmonary disease. Respir Res. 2013, 14, 67.
  79. Lester, R.D.; Jo, M.; Montel, V.; Takimoto, S.; Gonias, S.L. uPAR induces epithelial–mesenchymal transition in hypoxic breast cancer cells. J. Cell Biol. 2007, 178, 425–436.
  80. Hannan, R.T.; Miller, A.E.; Hung, R.-C.; Sano, C.; Peirce, S.M.; Barker, T.H. Extracellular matrix remodeling associated with bleomycin-induced lung injury supports pericyte-to-myofibroblast transition. Matrix Biol. Plus 2020, 10, 100056.
  81. Katoh, D.; Kozuka, Y.; Noro, A.; Ogawa, T.; Imanaka-Yoshida, K.; Yoshida, T. Tenascin-C Induces Phenotypic Changes in Fibroblasts to Myofibroblasts with High Contractility through the Integrin αvβ1/Transforming Growth Factor β/SMAD Signaling Axis in Human Breast Cancer. Am. J. Pathol. 2020, 190, 2123–2135.
  82. Bianchini, F.; Peppicelli, S.; Fabbrizzi, P.; Biagioni, A.; Mazzanti, B.; Menchi, G.; Calorini, L.; Pupi, A.; Trabocchi, A. Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells. Mol. Cell. Biochem. 2016, 424, 99–110.
  83. Borok, Z. Role for α3 integrin in EMT and pulmonary fibrosis. J. Clin. Investig. 2008, 119, 7–10.
  84. Shochet, G.E.; Brook, E.; Bardenstein-Wald, B.; Grobe, H.; Edelstein, E.; Israeli-Shani, L.; Shitrit, D. Integrin alpha-5 silencing leads to my-ofibroblastic differentiation in IPF-derived human lung fibroblasts. Ther. Adv. Chronic Dis. 2020, 24, 2040622320936023.
  85. Overstreet, J.M.; Wang, Y.; Wang, X.; Niu, A.; Gewin, L.S.; Yao, B.; Harris, R.C.; Zhang, M.Z. Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis. FASEB J. 2017, 31, 4407–4421.
  86. Xu, H.; Liu, L.; Cong, M.; Liu, T.; Sun, S.; Ma, H.; You, H.; Jia, J.; Wang, P. EGF neutralization antibodies attenuate liver fibrosis by inhibiting myofi-broblast proliferation in bile duct ligation mice. Histochem. Cell Biol. 2020, 154, 107–116.
  87. Shu, D.Y.; Lovicu, F.J. Enhanced EGF receptor-signaling potentiates TGFβ-induced lens epithelial-mesenchymal transition. Exp. Eye Res. 2019, 185, 107693.
  88. Wu, S.; Yang, S.; Qu, H. circ_CHFR regulates ox-LDL-mediated cell proliferation, apoptosis, and EndoMT by miR-15a-5p/EGFR axis in human brain microvessel endothelial cells. Open Life Sci. 2021, 16, 1053–1063.
  89. Thooyamani, A.S.; Mukhopadhyay, A. PDGFRα mediated survival of myofibroblasts inhibit satellite cell proliferation during aberrant regeneration of lacerated skeletal muscle. Sci. Rep. 2021, 11, 1–15.
  90. Jechlinger, M.; Sommer, A.; Moriggl, R.; Seither, P.; Kraut, N.; Capodiecci, P.; Donovan, M.; Cordon-Cardo, C.; Beug, H.; Grünert, S. Autocrine PDGFR signaling promotes mammary cancer metastasis. J. Clin. Investig. 2006, 116, 1561–1570.
  91. Yan, D.; Liu, X.; Xu, H.; Guo, S.-W. Platelets induce endothelial–mesenchymal transition and subsequent fibrogenesis in endometriosis. Reprod. Biomed. Online 2020, 41, 500–517.
  92. Chen, L.; Lin, G.; Chen, K.; Liang, R.; Wan, F.; Zhang, C.; Tian, G.; Zhu, X. VEGF promotes migration and invasion by regulating EMT and MMPs in nasopharyngeal carcinoma. J. Cancer 2020, 11, 7291–7301.
  93. Modi, S.; Tiwari, A.; Kulkarni, V. Reversal of TGF-β-induced epithelial-mesenchymal transition in hepatocellular carcinoma by sorafenib, a VEGFR-2 and Raf kinase inhibitor. Curr. Res. Pharmacol. Drug. Discov. 2021, 2, 100014.
  94. Rossato, F.A.; Su, Y.; Mackey, A.; Ng, Y.S.E. Fibrotic Changes and Endothelial-to-Mesenchymal Transition Promoted by VEGFR2 Antagonism Alter the Therapeutic Effects of VEGFA Pathway Blockage in a Mouse Model of Choroidal Neovascularization. Cells 2020, 9, 2057.
  95. Sanders, Y.Y.; Cui, Z.; Le Saux, C.J.; Horowitz, J.C.; Rangarajan, S.; Kurundkar, A.; Antony, V.B.; Thannickal, V.J. SMAD-Independent Down-Regulation of Caveolin-1 by TGF-β: Effects on Proliferation and Survival of Myofibroblasts. PLoS ONE 2015, 10, e0116995.
  96. Yang, S.; Zhao, J.; Huang, S.; Shu, B.; Yang, R.; Chen, L.; Xu, Y.; Xie, J.; Liu, X.; Jia, J. Reduced hydration-induced decreased caveolin-1 expression causes epithelial-to-mesenchymal transition. Am. J. Transl. Res. 2020, 12, 8067–8083.
  97. Jung, A.C.; Ray, A.M.; Ramolu, L.; Macabre, C.; Simon, F.; Noulet, F.; Blandin, A.F.; Renner, G.; Lehmann, M.; Choulier, L. Caveolin-1-negative head and neck squamous cell carcinoma primary tumors display increased epithelial to mesenchymal transition and prometastatic properties. Oncotarget 2015, 6, 41884–41901.
  98. Li, Z.; Wermuth, P.J.; Benn, B.S.; Lisanti, M.P.; Jimenez, S.A. Caveolin-1 Deficiency Induces Spontaneous Endothelial-to-Mesenchymal Transition in Murine Pulmonary Endothelial Cells in Vitro. Am. J. Pathol. 2012, 182, 325–331.
  99. Schnieder, J.; Mamazhakypov, A.; Birnhuber, A.; Wilhelm, J.; Kwapiszewska, G.; Ruppert, C.; Markart, P.; Wujak, L.; Rubio, K.; Barreto, G. Loss of LRP1 promotes acquisition of contractile-myofibroblast phenotype and release of active TGF-β1 from ECM stores. Matrix Biol. 2019, 88, 69–88.
  100. Hu, K.; Lin, L.; Tan, X.; Yang, J.; Bu, G.; Mars, W.M.; Liu, Y. tPA Protects Renal Interstitial Fibroblasts and Myofibroblasts from Apoptosis. J. Am. Soc. Nephrol. 2008, 19, 503–514.
  101. Hu, K.; Wu, C.; Mars, W.M.; Liu, Y. Tissue-type plasminogen activator promotes murine myofibroblast activation through LDL receptor–related protein 1–mediated integrin signaling. J. Clin. Investig. 2007, 117, 3821–3832.
  102. Omori, K.; Hattori, N.; Senoo, T.; Takayama, Y.; Masuda, T.; Nakashima, T.; Iwamoto, H.; Fujitaka, K.; Hamada, H.; Kohno, N. Inhibition of Plasminogen Activator Inhibitor-1 Attenuates Transforming Growth Factor-β-Dependent Epithelial Mesenchymal Transition and Differentiation of Fibroblasts to Myofibroblasts. PLoS ONE 2016, 11, e0148969.
  103. Zhang, Y.P.; Wang, W.L.; Liu, J.; Li, W.B.; Bai, L.L.; Yuan, Y.D.; Song, S.X. Plasminogen activator inhibitor-1 promotes the proliferation and inhibits the apoptosis of pulmonary fibroblasts by Ca2+ signaling. Thromb. Res. 2012, 131, 64–71.
  104. Masuda, T.; Nakashima, T.; Namba, M.; Yamaguchi, K.; Sakamoto, S.; Horimasu, Y.; Miyamoto, S.; Iwamoto, H.; Fujitaka, K.; Miyata, Y. Inhibition of PAI-1 limits chemotherapy resistance in lung cancer through suppressing myofibroblast characteristics of cancer-associated fibroblasts. J. Cell. Mol. Med. 2019, 23, 2984–2994.
  105. Pedroja, B.; Kang, L.; Imas, A.; Carmeliet, P.; Bernstein, A. Plasminogen activator inhibitor-1 regulates integrin alphavbeta3 ex-pression and autocrine transforming growth factor beta signaling. J. Biol. Chem. 2009, 284, 20708–20717.
  106. Ghosh, A.K.; Vaughan, D.E. PAI-1 in tissue fibrosis. J. Cell. Physiol. 2012, 227, 493–507.
  107. Ghosh, A.K.; Bradham, W.S.; Gleaves, L.A.; De Taeye, B.; Murphy, S.B.; Covington, J.W.; Vaughan, D.E. Genetic deficiency of plasminogen activator inhibitor-1 promotes cardiac fibrosis in aged mice: Involvement of constitutive transforming growth factor-beta signaling and endothelial-to-mesenchymal transition. Circulation 2010, 122, 1200–1209.
  108. Baumeier, C.; Escher, F.; Aleshcheva, G.; Pietsch, H.; Schultheiss, H.-P. Plasminogen activator inhibitor-1 reduces cardiac fibrosis and promotes M2 macrophage polarization in inflammatory cardiomyopathy. Basic Res. Cardiol. 2021, 116, 1–9.
  109. Kanno, Y.; Kawashita, E.; Kokado, A.; Okada, K.; Ueshima, S.; Matsuo, O.; Matsuno, H. Alpha2-antiplasmin regulates the development of dermal fibrosis in mice by prostaglandin F2α synthesis through adipose triglyceride lipase/calcium-independent phospho-lipase. Arthritis Rheum. 2013, 65, 492–502.
  110. Kanno, Y.; Shu, E.; Kanoh, H.; Seishima, M. The Antifibrotic Effect of α2AP Neutralization in Systemic Sclerosis Dermal Fibroblasts and Mouse Models of Systemic Sclerosis. J. Investig. Dermatol. 2015, 136, 762–769.
  111. Kanno, Y.; Shu, E.; Niwa, H.; Seishima, M.; Ozaki, K.-I. MicroRNA-30c attenuates fibrosis progression and vascular dysfunction in systemic sclerosis model mice. Mol. Biol. Rep. 2021, 48, 3431–3437.
  112. Kanno, Y.; Hirota, M.; Matsuo, O.; Ozaki, K.-I. α2-antiplasmin positively regulates endothelial-to-mesenchymal transition and fibrosis progression in diabetic nephropathy. Mol. Biol. Rep. 2021, 49, 205–215.
  113. Zhao, X.; Chen, J.; Sun, H.; Zhang, Y.; Zou, D. New insights into fibrosis from the ECM degradation perspective: The macro-phage-MMP-ECM interaction. Cell Biosci. 2022, 12, 117.
  114. Michalczyk, K.; Cymbaluk-Płoska, A. Metalloproteinases in Endometrial Cancer-Are They Worth Measuring? Int. J. Mol. Sci. 2021, 22, 12472.
  115. Niwa, H.; Kanno, Y.; Shu, E.; Seishima, M. Decrease in matrix metalloproteinase-3 activity in systemic sclerosis fibroblasts causes α2-antiplasmin and extracellular matrix deposition, and contributes to fibrosis development. Mol. Med. Rep. 2020, 22, 3001–3007.
  116. Lijnen, H.R. Matrix Metalloproteinases and Cellular Fibrinolytic Activity. Biochemistry 2002, 67, 92–98.
  117. Menou, A.; Duitman, J.; Crestani, B. The impaired proteases and anti-proteases balance in Idiopathic Pulmonary Fibrosis. Matrix Biol. 2018, 68-69, 382–403.
  118. Newby, A.C. Metalloproteinase production from macrophages—A perfect storm leading to atherosclerotic plaque rupture and myocardial infarction. Exp. Physiol. 2016, 101, 1327–1337.
  119. Okazaki, I.; Noro, T.; Tsutsui, N.; Yamanouchi, E.; Kuroda, H.; Nakano, M.; Yokomori, H.; Inagaki, Y. Fibrogenesis and Carcinogenesis in Nonalcoholic Steatohepatitis (NASH): Involvement of Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinase (TIMPs). Cancers 2014, 6, 1220–1255.
  120. Waszczykowska, A.; Podgórski, M.; Waszczykowski, M.; Gerlicz-Kowalczuk, Z.; Jurowski, P. Matrix Metalloproteinases MMP-2 and MMP-9, Their Inhibitors TIMP-1 and TIMP-2, Vascular Endothelial Growth Factor and sVEGFR-2 as Predictive Markers of Ischemic Retinopathy in Patients with Systemic Sclerosis-Case Series Report. Int. J. Mol. Sci. 2020, 21, 8703.
  121. Young-Min, A.S.; Beeton, C.; Laughton, R.; Plumpton, T.; Bartram, S.; Murphy, G.; Black, C.; Cawston, E.T. Serum TIMP-1, TIMP-2, and MMP-1 in patients with systemic sclerosis, primary Raynaud’s phenomenon, and in normal controls. Ann. Rheum. Dis. 2001, 60, 846–851.
  122. Yao, H.; Yang, X.; Yan, M.; Fang, X.; Wang, Y.; Qi, H.; Sun, L. Correlation of Serum M-CSF, CER, and TIMP-1 Levels with Liver Fibrosis in Viral Hepatitis. Comput. Math. Methods Med. 2022, 2022, 6736225.
  123. Eguchi, A.; Iwasa, M.; Sugimoto, R.; Tempaku, M.; Yoshikawa, K.; Yoshizawa, N.; Povero, D.; Sugimoto, K.; Hasegawa, H.; Takei, Y. Complement complex 1 subunit q-mediated hepatic stellate cell activation with connective tissue growth factor elevation is a prognostic factor for survival in rat and human chronic liver diseases. Hepatol. Commun. 2022, 6, 3515–3527.
  124. Lefeuvre, C.; Roux, M.; Blanchard, S.; Le Guillou-Guillemette, H.; Boursier, J.; Lunel-Fabiani, F.; Jeannin, P.; Pivert, A.; Ducancelle, A. Analysis of hepatic fibrosis markers in the serum of chronic hepatitis B patients according to basal core promoter/precore mutants. Sci. Rep. 2022, 12, 10261.
  125. Yang, K.; Palm, J.; König, J.; Seeland, U.; Rosenkranz, S.; Feiden, W.; Rübe, C.; Rübe, C.E. Matrix-Metallo-Proteinases and their tissue inhibitors in radiation-induced lung injury. Int. J. Radiat. Biol. 2007, 83, 665–676.
  126. Wang, Y.; Huang, G.; Mo, B.; Wang, C. Artesunate modulates expression of matrix metalloproteinases and their inhibitors as well as collagen-IV to attenuate pulmonary fibrosis in rats. Genet. Mol. Res. 2016, 15, 530.
  127. Kökény, G.; Németh, Á.; Kopp, J.B.; Chen, W.; Oler, A.J.; Manzéger, A.; Rosivall, L.; Mózes, M.M. Susceptibility to kidney fibrosis in mice is associated with early growth response-2 protein and tissue inhibitor of metalloproteinase-1 expression. Kidney Int. 2022, 102, 337–354.
  128. Takawale, A.; Zhang, P.; Patel, V.; Wang, X.; Oudit, G.; Kassiri, Z. Tissue Inhibitor of Matrix Metalloproteinase-1 Promotes Myo-cardial Fibrosis by Mediating CD63-Integrin β1 Interaction. Hypertension 2017, 69, 1092–1103.
  129. Kanno, Y.; Shu, E.; Niwa, H.; Kanoh, H.; Seishima, M. Alternatively activated macrophages are associated with the α2AP production that occurs with the development of dermal fibrosis: The role of alternatively activated macrophages on the development of fibrosis. Arthritis Res Ther. 2020, 22, 76.
  130. Kanno, Y.; Kawashita, E.; Minamida, M.; Kaneiwa, A.; Okada, K.; Ueshima, S.; Matsuo, O.; Matsuno, H. Alpha2-antiplasmin is associated with the pro-gression of fibrosis. Am. J. Pathol. 2010, 176, 238–245.
  131. Kanno, Y.; Miyashita, M.; Seishima, M.; Matsuo, O. α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses. Immun. Inflamm. Dis. 2020, 8, 267–278.
  132. Rabieian, R.; Boshtam, M.; Zareei, M.; Kouhpayeh, S.; Masoudifar, A.; Mirzaei, H. Plasminogen Activator Inhibitor Type-1 as a Regulator of Fibrosis. J. Cell Biochem. 2018, 119, 17–27.
  133. Ueno, M.; Maeno, T.; Nomura, M.; Aoyagi-Ikeda, K.; Matsui, H.; Hara, K.; Tanaka, T.; Iso, T.; Suga, T.; Kurabayashi, M. Hypoxia-inducible factor-1α mediates TGF-β-induced PAI-1 production in alveolar macrophages in pulmonary fibrosis. Am. J. Physiol. Cell. Mol. Physiol. 2011, 300, L740–L752.
  134. Ma, L.; Fogo, A. PAI-1 and kidney fibrosis. Front. Biosci. 2009, 14, 2028–2041.
  135. Liakouli, V.; Cipriani, P.; Marrelli, A.; Alvaro, S.; Ruscitti, P.; Giacomelli, R. Angiogenic cytokines and growth factors in systemic sclerosis. Autoimmun. Rev. 2011, 10, 590–594.
  136. Mostmans, Y.; Cutolo, M.; Giddelo, C.; Decuman, S.; Melsens, K.; Declercq, H.; Vandecasteele, E.; De Keyser, F.; Distler, O.; Gutermuth, J. The role of endothelial cells in the vasculopathy of systemic sclerosis: A systematic review. Autoimmun. Rev. 2017, 16, 774–786.
  137. Zanin-Silva, D.C.; Santana-Gonçalves, M.; Kawashima-Vasconcelos, M.Y.; Oliveira, M.C. Management of Endothelial Dysfunction in Systemic Sclerosis: Current and Developing Strategies. Front. Med. 2021, 8, 250.
  138. Plow, E.F.; Hoover-Plow, J. The Functions of Plasminogen in Cardiovascular Disease. Trends Cardiovasc. Med. 2004, 14, 180–186.
  139. Mosesson, M.W. Fibrinogen and fibrin structure and functions. J. Thromb. Haemost. 2005, 3, 1894–1904.
  140. Rundhaug, J.E. Matrix metalloproteinases and angiogenesis. J. Cell. Mol. Med. 2005, 9, 267–285.
  141. Yan, Q.; Sage, E. Transforming growth factor-beta1 induces apoptotic cell death in cultured retinal endothelial cells but not pericytes: Association with decreased expression of p21waf1/cip. J. Cell Biochem. 1998, 70, 70–83.
  142. Long, D.; Yang, J.; Wu, X.; Gui, Y.; Yu, L. Urokinase-type plasminogen activator protects human umbilical vein endothelial cells from apoptosis in sepsis. Int. J. Clin. Exp. Pathol. 2019, 12, 77–86.
  143. Prager, G.W.; Mihaly, J.; Brunner, P.M.; Koshelnick, Y.; Hoyer-Hansen, G.; Binder, B.R. Urokinase mediates endothelial cell survival via induction of the X-linked inhibitor of apoptosis protein. Blood 2009, 113, 1383–1390.
  144. Song, T.; Meng, S.; Xu, S.-T.; Jin, S.-J.; Zeng, Q.-Z.; Gu, G.-J. The overexpression of uPA promotes the proliferation and fibrinolytic activity of human umbilical vein endothelial cells. Int. J. Clin. Exp. Pathol. 2019, 12, 2959–2966.
  145. Beloglazova, I.B.; Zubkova, E.S.; Stambol’skii, D.V.; Plekhanova, O.S.; Men’shikov, M.Y.; Akopyan, Z.A.; Bibilashvili, R.S.; Parfenova, E.V.; Tkachuk, V.A. Proteolytically inactive recom-binant forms of urokinase suppress migration of endothelial cells. Bull. Exp. Biol. Med. 2014, 156, 756–759.
  146. Balsara, R.D.; Merryman, R.; Virjee, F.; Northway, C.; Castellino, F.J.; Ploplis, A.V. A deficiency of uPAR alters endothelial angiogenic function and cell morphology. Vasc. Cell 2011, 3, 10.
  147. Lu, H.; Mabilat, C.; Yeh, P.; Guitton, J.D.; Li, H.; Pouchelet, M.; Shoevaert, D.; Legrand, Y.; Soria, J.; Soria, C. Blockage of urokinase receptor reduces in vitro the motility and the deformability of endothelial cells. FEBS Lett. 1996, 380, 21–24.
  148. Beloglazova, I.; Stepanova, V.; Zubkova, E.; Dergilev, K.; Koptelova, N.; Tyurin-Kuzmin, P.A.; Dyikanov, D.; Plekhanova, O.; Cines, D.B.; Mazar, A.P. Mesenchymal stromal cells enhance self-assembly of a HUVEC tubular network through uPA-uPAR/VEGFR2/integrin/NOTCH crosstalk. Biochim. Biophys. Acta. Mol. Cell Res. 2022, 1869, 119157.
  149. Alexander, R.A.; Prager, G.W.; Mihaly-Bison, J.; Uhrin, P.; Sunzenauer, S.; Binder, B.R.; Schütz, G.J.; Freissmuth, M.; Breuss, J.M. VEGF-induced endothelial cell migration requires urokinase receptor (uPAR)-dependent integrin redistribution. Cardiovasc. Res. 2012, 94, 125–135.
  150. Reuning, U.; Sperl, S.; Kopitz, C.; Kessler, H.; Krüger, A.; Schmitt, M.; Magdolen, V. Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR): Development of Antagonists of uPA / uPAR Interaction and their Effects In Vitro and In Vivo. Curr. Pharm. Des. 2003, 9, 1529–1543.
  151. Poettler, M.; Unseld, M.; Mihaly-Bison, J.; Uhrin, P.; Koban, F.; Binder, B.R.; Zielinski, C.C.; Prager, G.W. The urokinase receptor (CD87) represents a central mediator of growth factor-induced endothelial cell migration. Thromb. Haemost. 2012, 108, 357–366.
  152. Stepanova, V.; Jayaraman, P.S.; Zaitsev, S.V.; Lebedeva, T.; Bdeir, K.; Kershaw, R.; Holman, K.R.; Parfyonova, Y.V.; Semina, E.V.; Beloglazova, I.B. Urokinase-type Plasminogen Activator (uPA) Promotes Angiogenesis by Attenuating Proline-rich Homeodomain Protein (PRH) Transcription Factor Activity and De-repressing Vascular Endothelial Growth Factor (VEGF) Receptor Expression. J. Biol. Chem. 2016, 291, 15029–15045.
  153. Raghu, H.; Nalla, A.K.; Gondi, C.S.; Gujrati, M.; Dinh, D.H.; Rao, J.S. uPA and uPAR shRNA inhibit angiogenesis via enhanced secretion of SVEGFR1 independent of GM-CSF but dependent on TIMP-1 in endothelial and glioblastoma cells. Mol. Oncol. 2011, 6, 33–47.
  154. Park, J.; Keller, G.; Ferrara, N. The vascular endothelial growth factor (VEGF) isoforms: Differential deposition into the subep-ithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol. Biol. Cell. 1993, 4, 1317–1326.
  155. Kanno, Y.; Shu, E.; Kanoh, H.; Matsuda, A.; Seishima, M. α2AP regulates vascular alteration by inhibiting VEGF signaling in systemic sclerosis: The roles of α2AP in vascular dysfunction in systemic sclerosis. Arthritis Res. Ther. 2017, 19, 1–8.
  156. Herkenne, S.; Paques, C.; Nivelles, O.; Lion, M.; Bajou, K.; Pollenus, T.; Fontaine, M.; Carmeliet, P.; Martial, J.A.; Nguyen, N.Q. The interaction of uPAR with VEGFR2 promotes VEGF-induced angiogenesis. Sci. Signal. 2015, 8, ra117.
  157. Larusch, G.A.; Merkulova, A.; Mahdi, F.; Shariat-Madar, Z.; Sitrin, R.G.; Cines, D.B.; Schmaier, A.H. Domain 2 of uPAR regulates single-chain uro-kinase-mediated angiogenesis through β1-integrin and VEGFR. Am. J. Physiol. Heart Circ. Physiol. 2013, 305, H305–H320.
  158. LaRusch, G.A.; Mahdi, F.; Shariat-Madar, Z.; Adams, G.; Sitrin, R.G.; Zhang, W.M.; McCrae, K.R.; Schmaier, A.H. Factor XII stimulates ERK1/2 and Akt through uPAR, integrins, and the EGFR to initiate angiogenesis. Blood 2010, 115, 5111–5120.
  159. D’Alessio, S.; Fibbi, G.; Cinelli, M.; Guiducci, S.; Del Rosso, A.; Margheri, F.; Serratì, S.; Pucci, M.; Kahaleh, B.; Fan, P. Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis. Arthritis Rheum. 2004, 50, 3275–3285.
  160. Bifulco, K.; Longanesi-Cattani, I.; Gala, M.; DICarluccio, G.; Masucci, M.T.; Pavone, V.; Lista, L.; Arra, C.; Stoppelli, M.P.; Carriero, M.V. The soluble form of urokinase receptor promotes angiogenesis through its Ser⁸⁸-Arg-Ser-Arg-Tyr⁹² chemotactic sequence. J. Thromb. Haemost. 2010, 8, 2789–2799.
  161. Fuchs, P.Ö.; Calitz, C.; Pavlović, N.; Binet, F.; Solbak, S.M.Ø.; Danielson, U.H.; Kreuger, J.; Heindryckx, F.; Gerwins, P. Fibrin fragment E potentiates TGF-β-induced myofibroblast activation and recruitment. Cell Signal. 2020, 72, 109661.
  162. Schimmel, K.; Ichimura, K.; Reddy, S.; Haddad, F.; Spiekerkoetter, E. Cardiac Fibrosis in the Pressure Overloaded Left and Right Ventricle as a Therapeutic Target. Front. Cardiovasc. Med. 2022, 9, 6553.
  163. Liu, S.-F.; Veetil, N.N.; Li, Q.; Kucherenko, M.M.; Knosalla, C.; Kuebler, W.M. Pulmonary hypertension: Linking inflammation and pulmonary arterial stiffening. Front. Immunol. 2022, 13, 209.
  164. Christou, H.; Khalil, R.A. Mechanisms of pulmonary vascular dysfunction in pulmonary hypertension and implications for novel therapies. Am. J. Physiol. Circ. Physiol. 2022, 322, H702–H724.
  165. Ban, C.; Wang, T.; Zhang, S.; Xin, P.; Liang, L.; Wang, C.; Dai, H. Fibrinolytic system related to pulmonary arterial pressure and lung function of patients with idiopathic pulmonary fibrosis. Clin. Respir. J. 2015, 11, 640–647.
  166. Levi, M.; Moons, L.; Bouché, A.; Shapiro, S.D.; Collen, D.; Carmeliet, P. Deficiency of Urokinase-Type Plasminogen Activator–Mediated Plasmin Generation Impairs Vascular Remodeling During Hypoxia-Induced Pulmonary Hypertension in Mice. Circulation 2001, 103, 2014–2020.
  167. Manetti, M.; Allanore, Y.; Revillod, L.; Fatini, C.; Guiducci, S.; Cuomo, G.; Bonino, C.; Riccieri, V.; Bazzichi, L.; Liakouli, V. A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis. Arthritis Rheum. 2010, 63, 247–256.
  168. Makarova, A.M.; Lebedeva, T.V.; Nassar, T.; Higazi, A.A.; Xue, J.; Carinato, M.E.; Bdeir, K.; Cines, D.B.; Stepanova, V. Urokinase-type Plasminogen Activator (uPA) Induces Pulmonary Microvascular Endothelial Permeability through Low Density Lipoprotein Receptor-related Protein (LRP)-dependent Activation of Endothelial Nitric-oxide Synthase. J. Biol. Chem. 2011, 286, 23044–23053.
  169. Boccella, S.; Panza, E.; Lista, L.; Belardo, C.; Ianaro, A.; De Rosa, M.; de Novellis, V.; Pavone, V. Preclinical evaluation of the urokinase receptor-derived peptide UPARANT as an anti-inflammatory drug. Inflamm. Res. 2017, 66, 701–709.
  170. Yoon, S.Y.; Lee, Y.J.; Seo, J.H.; Sung, H.J.; Park, K.H.; Choi, I.K.; Kim, S.J.; Oh, S.C.; Choi, C.W.; Kim, B.S. uPAR expression under hypoxic conditions depends on iNOS modulated ERK phosphorylation in the MDA-MB-231 breast carcinoma cell line. Cell Res. 2006, 16, 75–81.
  171. Huang, E.; Peng, N.; Xiao, F.; Hu, D.; Wang, X.; Lu, L. The Roles of Immune Cells in the Pathogenesis of Fibrosis. Int. J. Mol. Sci. 2020, 21, 5203.
  172. Abdul, S.; Leebeek, F.; Rijken, D.; Uitte de Willige, S. Natural heterogeneity of α2-antiplasmin: Functional and clinical conse-quences. Blood 2016, 127, 538–545.
  173. Van Geffen, C.; Deißler, A.; Quante, M.; Renz, H.; Hartl, D.; Kolahian, S. Regulatory Immune Cells in Idiopathic Pulmonary Fibrosis: Friends or Foes? Front. Immunol. 2021, 22, 663203.
  174. Brown, M.; O’Reilly, S. The immunopathogenesis of fibrosis in systemic sclerosis. Clin. Exp. Immunol. 2018, 195, 310–321.
  175. Pattanaik, D.; Brown, M.; Postlethwaite, B.; Postlethwaite, A. Pathogenesis of Systemic Sclerosis. Front Immunol. 2015, 6, 272.
  176. Numajiri, H.; Kuzumi, A.; Fukasawa, T.; Ebata, S.; Yoshizaki-Ogawa, A.; Asano, Y.; Kazoe, Y.; Mawatari, K.; Kitamori, T.; Yoshizaki, A. B Cell Depletion Inhibits Fibrosis via Suppression of Profibrotic Macrophage Differentiation in a Mouse Model of Systemic Sclerosis. Arthritis Rheumatol. 2021, 73, 2086–2095.
  177. Nakayama, W.; Jinnin, M.; Makino, K.; Kajihara, I.; Makino, T.; Fukushima, S.; Inoue, Y.; Ihn, H. Serum levels of soluble CD163 in patients with systemic sclerosis. Rheumatol. Int. 2010, 32, 403–407.
  178. Wang, X.; Chen, J.; Xu, J.; Xie, J.; Harris, D.C.H.; Zheng, G. The Role of Macrophages in Kidney Fibrosis. Front. Physiol. 2021, 12, 5838.
  179. Mosser, D.M.; Edwards, J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008, 8, 958–969.
  180. Mondino, A.; Blasi, F. uPA and uPAR in fibrinolysis, immunity and pathology. Trends Immunol. 2004, 25, 450–455.
  181. Syrovets, T.; Lunov, O.; Simmet, T. Plasmin as a proinflammatory cell activator. J. Leukoc. Biol. 2012, 92, 509–519.
  182. Medcalf, R.; Keragala, C. Fibrinolysis: A Primordial System Linked to the Immune Response. Int. J. Mol. Sci. 2021, 22, 3406.
  183. Hastings, S.; Myles, P.; Medcalf, R. Plasmin, Immunity, and Surgical Site Infection. J. Clin. Med. 2021, 10, 2070.
  184. Vago, J.P.; Sugimoto, M.A.; Lima, K.M.; Negreiros-Lima, G.L.; Baik, N.; Teixeira, M.M.; Perretti, M.; Parmer, R.J.; Miles, L.A.; Sousa, L.P. Plasminogen and the Plasminogen Receptor, Plg-RKT, Regulate Macrophage Phenotypic, and Functional Changes. Front. Immunol. 2019, 10, 1458.
  185. Shimazu, H.; Munakata, S.; Tashiro, Y.; Salama, Y.; Dhahri, D.; Eiamboonsert, S.; Ota, Y.; Onoda, H.; Tsuda, Y.; Okada, Y. Pharmacological targeting of plasmin prevents lethality in a murine model of macrophage activation syndrome. Blood 2017, 130, 59–72.
  186. Li, X.; Syrovets, T.; Genze, F.; Pitterle, K.; Oberhuber, A.; Orend, K.H.; Simmet, T. Plasmin Triggers Chemotaxis of Monocyte-Derived Dendritic Cells Through an Akt2-Dependent Pathway and Promotes a T-Helper Type-1 Response. Arter. Thromb. Vasc. Biol. 2010, 30, 582–590.
  187. Bryer, S.C.; Fantuzzi, G.; Van Rooijen, N.; Koh, T.J. Urokinase-Type Plasminogen Activator Plays Essential Roles in Macrophage Chemotaxis and Skeletal Muscle Regeneration. J. Immunol. 2008, 180, 1179–1188.
  188. Meznarich, J.; Malchodi, L.; Helterline, D.; Ramsey, S.A.; Bertko, K.; Plummer, T.; Plawman, A.; Gold, E.; Stempien-Otero, A. Urokinase Plasminogen Activator Induces Pro-Fibrotic/M2 Phenotype in Murine Cardiac Macrophages. PLoS ONE 2013, 8, e57837.
  189. Kanno, Y.; Ishisaki, A.; Miyashita, M.; Matsuo, O. The blocking of uPAR suppresses lipopolysaccharide-induced inflammatory osteoclastogenesis and the resultant bone loss through attenuation of integrin β3/Akt pathway. Immun. Inflamm. Dis. 2016, 4, 338–349.
  190. Liu, G.; Yang, Y.; Yang, S.; Banerjee, S.; De Freitas, A.; Friggeri, A.; Davis, K.I.; Abraham, E. The receptor for urokinase regulates TLR2 mediated in-flammatory responses in neutrophils. PLoS ONE 2011, 6, e25843.
  191. Li, J.; Pan, Y.; Li, D.; Xia, X.; Jiang, Q.; Dou, H.; Hou, Y. Urokinase-type plasminogen activator receptor is required for impairing toll-like receptor 7 signaling on macrophage efferocytosis in lupus. Mol. Immunol. 2020, 127, 38–45.
  192. Kiyan, Y.; Tkachuk, S.; Rong, S.; Gorrasi, A.; Ragno, P.; Dumler, I.; Haller, H.; Shushakova, N. TLR4 Response to LPS Is Reinforced by Urokinase Receptor. Front. Immunol. 2020, 11, 3550.
  193. Rasmussen, L.J.H.; Petersen, J.E.V.; Eugen-Olsen, J. Soluble Urokinase Plasminogen Activator Receptor (suPAR) as a Biomarker of Systemic Chronic Inflammation. Front. Immunol. 2021, 12, 641.
  194. Yousif, A.M.; Minopoli, M.; Bifulco, K.; Ingangi, V.; Di Carluccio, G.; Merlino, F.; Motti, M.L.; Grieco, P.; Carriero, M.V. Cyclization of the Urokinase Receptor-Derived Ser-Arg-Ser-Arg-Tyr Peptide Generates a Potent Inhibitor of Trans-Endothelial Migration of Monocytes. PLoS ONE 2015, 10, e0126172.
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