Protease-activated receptors-1 and -2 can mediate endothelial barrier protection: role in factor Xa signaling

Feistritzer, Clemens; Lenta, R.; Riewald, Matthias

doi:10.1111/j.1538-7836.2005.01610.x

Cited by 83 publications

(87 citation statements)

References 53 publications

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“…3,4,[20][21][22] FXa-mediated endothelial barrier protective effects were of similar magnitude to those induced by APC ( Figure 4D). The protective effects by FXa were time dependent, and the most effective barrier protection was observed after 2 to 3 hours ( Figure 4E).…”

Section: Fxa-mediated Changes In Endothelial Barrier Integritysupporting

confidence: 54%

“…Previous studies implicated both PAR1 and PAR2 for FXa-mediated barrier protective signaling responses in endothelial cells. [20][21][22] However, FXa-induced endothelial barrier protection required PAR1 but not PAR2 when barrier disruption was induced by the high affinity "TFLLRN…" TRAP peptide 26 that induced robust barrier disruption ( Figure 4H). In contrast, FXa-induced endothelial barrier protection was dependent on both PAR1 and PAR2 when barrier disruption was induced by the natural "SFLLRN…" TRAP tethered ligand ( Figure 4I), in agreement with previous reports.…”

Section: Org Frommentioning

confidence: 99%

“…[20][21][22] To understand how PAR1 and PAR3 cleavage at Arg41 contributes to FXa's effects on barrier function, changes in ECIS using the iCelligence system were monitored in EA.hy926 cells. This system provides the advantage of real-time monitoring of the disruption and recovery of the endothelial barrier function (supplemental Figure 1).…”

Section: Fxa-mediated Changes In Endothelial Barrier Integritymentioning

confidence: 99%

“…Similar to APC, FXa mediates endothelial barrier protective effects that involve both PAR1, PAR2, and EPCR. [20][21][22] To date, however, no potential role for PAR3 in FXa-induced barrier integrity has been implicated. Analysis of the FXa PAR1 and PAR3 proteolysis profiles revealed a unique crossover cleavage pattern between that of thrombin and APC.…”

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confidence: 99%

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Noncanonical PAR3 activation by factor Xa identifies a novel pathway for Tie2 activation and stabilization of vascular integrity

Stavenuiter

Mosnier

2014

Blood

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• Factor Xa activates PAR3 in the presence of EPCR by noncanonical cleavage at Arg41.• Noncanonical PAR3 activation induces Tie2 activation, upregulation and redistribution of ZO-1, and stabilization of tight junctions.Endothelial barrier protective effects of activated protein C (APC) require the endothelial protein C receptor (EPCR), protease-activated receptor (PAR) 1, and PAR3. In contrast, PAR1 and PAR3 activation by thrombin results in barrier disruption. Noncanonical PAR1 and PAR3 activation by APC vs canonical activation by thrombin provides an explanation for the functional selectivity of these proteases. Here we found that factor Xa (FXa) activated PAR1 at canonical Arg41 similar to thrombin but cleaved PAR3 at noncanonical Arg41 similar to APC. This unique PAR1-PAR3 activation profile permitted the identification of noncanonical PAR3 activation as a novel activation pathway for barrier protective tunica intima endothelial receptor tyrosine kinase 2 (Tie2). APC, FXa, and the noncanonical PAR3 tetheredligand peptide induced prolonged activation of Tie2, whereas thrombin and the canonical PAR3 tethered-ligand peptide did not. Tie2 activation by FXa required PAR3 and EPCR. FXa and the noncanonical PAR3 tethered-ligand peptide induced Tie2-and PAR3-dependent upregulation of tight-junction-associated protein zona occludens 1 (ZO-1), translocation of ZO-1 to cell-cell borders, and the formation of typical ZO-1 honeycomb patterns that are indicative of tight-junction stabilization. These data provide intriguing novel insights into the diversification of functional selectivity of protease signaling achievable by canonical and noncanonical PAR activation, such as the activation of vascular-protective Tie2 by noncanonical PAR3 activation. (Blood. 2014;124(23):3480-3489) Introduction Protease-activated receptors (PARs) are G protein-coupled receptors that comprise a subfamily of 4 receptors (PAR1, PAR2, PAR3, and PAR4). The PARs are unique in that they carry their own encrypted ligand encoded in the extracellular N-terminal tail. Proteolysis by coagulation or vascular proteases creates a new N-terminal tethered ligand that activates the PAR. Multiple proteases can activate PARs with each protease displaying a unique specificity for the different receptors.1 Efficient activation of PAR1 by thrombin is driven by binding of exosite I to the hirudin-like sequence of PAR1, thereby optimally positioning Arg41 in the active site of thrombin.2 Other proteases make use of coreceptors for efficient PAR activation. For instance, tissue factor permits PAR1 and PAR2 activation by the ternary complex, and the endothelial protein C receptor (EPCR) enhances activation of PAR1, PAR2, and PAR3 by activated protein C (APC). 3-5The requirement of PAR1 for APC's cytoprotective effects created a conundrum because PAR1 activation by thrombin generally results in opposite proinflammatory and endothelial barrier disruptive effects. 5,6The discordant effects of PAR1 activation by thrombin vs APC are perhaps most apparent for the regula...

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Section: Fxa-mediated Changes In Endothelial Barrier Integritysupporting

confidence: 54%

Section: Org Frommentioning

confidence: 99%

Section: Fxa-mediated Changes In Endothelial Barrier Integritymentioning

confidence: 99%

mentioning

confidence: 99%

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Noncanonical PAR3 activation by factor Xa identifies a novel pathway for Tie2 activation and stabilization of vascular integrity

Stavenuiter

Mosnier

2014

Blood

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“…The molecular mechanisms underlying the cytoprotective effects of APC have not been fully characterized but appear mediated independently of its anticoagulant function (8). Through mechanisms downstream of PAR-1 activation, APC has been shown to exhibit anti-inflammatory and anti-apoptotic properties via up-regulated gene expression of anti-apoptotic and anti-inflammatory mediators (9,10), down-regulation of pro-inflammatory cytokines (10,11), and stabilization of endothelial barrier function (12,13).…”

mentioning

confidence: 99%

Dissociation of Activated Protein C Functions by Elimination of Protein S Cofactor Enhancement

Harmon

Preston

Áinle

et al. 2008

Journal of Biological Chemistry

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Activated protein C (APC) plays a critical anticoagulant role in vivo by inactivating procoagulant factor Va and factor VIIIa and thus down-regulating thrombin generation. In addition, APC bound to the endothelial cell protein C receptor can initiate protease-activated receptor-1 (PAR-1)-mediated cytoprotective signaling. Protein S constitutes a critical cofactor for the anticoagulant function of APC but is not known to be involved in regulating APC-mediated protective PAR-1 signaling. In this study we utilized a site-directed mutagenesis strategy to characterize a putative protein S binding region within the APC Gla domain. Three single amino acid substitutions within the APC Gla domain (D35T, D36A, and A39V) were found to mildly impair protein S-dependent anticoagulant activity (<2-fold) but retained entirely normal cytoprotective activity. However, a single amino acid substitution (L38D) ablated the ability of protein S to function as a cofactor for this APC variant. Consequently, in assays of protein S-dependent factor Va proteolysis using purified proteins or in the plasma milieu, APC-L38D variant exhibited minimal residual anticoagulant activity compared with wild type APC. Despite the location of Leu-38 in the Gla domain, APC-L38D interacted normally with endothelial cell protein C receptor and retained its ability to trigger PAR-1 mediated cytoprotective signaling in a manner indistinguishable from that of wild type APC. Consequently, elimination of protein S cofactor enhancement of APC anticoagulant function represents a novel and effective strategy by which to separate the anticoagulant and cytoprotective functions of APC for potential therapeutic gain.

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Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models

Parker

2011

Comprehensive Physiology

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Acute lung injury is a general term that describes injurious conditions that can range from mild interstitial edema to massive inflammatory tissue destruction. This review will cover theoretical considerations and quantitative and semi-quantitative methods for assessing edema formation and increased vascular permeability during lung injury. Pulmonary edema can be quantitated directly using gravimetric methods, or indirectly by descriptive microscopy, quantitative morphometric microscopy, altered lung mechanics, high-resolution computed tomography, magnetic resonance imaging, positron emission tomography, or x-ray films. Lung vascular permeability to fluid can be evaluated by measuring the filtration coefficient (Kf) and permeability to solutes evaluated from their blood to lung clearances. Albumin clearances can then be used to calculate specific permeability-surface area products (PS) and reflection coefficients (σ). These methods as applied to a wide variety of transgenic mice subjected to acute lung injury by hyperoxic exposure, sepsis, ischemia-reperfusion, acid aspiration, oleic acid infusion, repeated lung lavage, and bleomycin are reviewed. These commonly used animal models simulate features of the acute respiratory distress syndrome, and the preparation of genetically modified mice and their use for defining specific pathways in these disease models are outlined. Although the initiating events differ widely, many of the subsequent inflammatory processes causing lung injury and increased vascular permeability are surprisingly similar for many etiologies.

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Protease-activated receptors-1 and -2 can mediate endothelial barrier protection: role in factor Xa signaling

Cited by 83 publications

References 53 publications

Noncanonical PAR3 activation by factor Xa identifies a novel pathway for Tie2 activation and stabilization of vascular integrity

Noncanonical PAR3 activation by factor Xa identifies a novel pathway for Tie2 activation and stabilization of vascular integrity

Dissociation of Activated Protein C Functions by Elimination of Protein S Cofactor Enhancement

Acute Lung Injury and Pulmonary Vascular Permeability: Use of Transgenic Models

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