Vasodilator‐stimulated phosphoprotein deficiency potentiates PAR‐1‐induced increase in endothelial permeability in mouse lungs

Profirovic, Jasmina; Han, Jing‐Yan; Андреева, А. В.; Neamu, Radu; Pavlovic, Sasha; Vogel, Stephen M.; Walter, Ulrich; Voyno-Yasenetskaya, Tatyana A.

doi:10.1002/jcp.22453

Cited by 7 publications

(7 citation statements)

References 39 publications

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“…Profirovic et al . extended these findings demonstrating increased vascular permeability in response to thrombin in VASP −/− deficient lungs [43]. We now demonstrate that VASP −/− animals do not demonstrate a difference in vascular permeability at baseline but have increased vascular permeability during a hypoxic challenge.…”

Section: Discussionsupporting

confidence: 82%

Vasodilator Phosphostimulated Protein (VASP) Protects Endothelial Barrier Function During Hypoxia

et al. 2011

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The endothelial barrier controls the passage of solutes from the vascular space. This is achieved through active reorganization of the actin cytoskeleton. A central cytoskeletal protein involved into this is vasodilator-stimulated phosphoprotein (VASP). However, the functional role of endothelial VASP during hypoxia has not been thoroughly elucidated. We determined endothelial VASP expression through real-time PCR (Rt-PCR), immunhistochemistry, and Western blot analysis during hypoxia. VASP promoter studies were performed using a PGL3 firefly luciferase containing plasmid. Following approval by the local authorities, VASP−/− mice and littermate controls were subjected to normobaric hypoxia (8% O2, 92% N2) after intravenous injection of Evans blue dye. In in vitro studies, we found significant VASP repression in human microvascular and human umbilical vein endothelial cells through Rt-PCR, immunhistochemistry, and Western blot analysis. The VASP promoter construct demonstrated significant repression in response to hypoxia, which was abolished when the binding of hypoxia-inducible factor 1 alpha was excluded. Exposure of wild-type (WT) and VASP−/− animals to normobaric hypoxia for 4 h resulted in an increase in Evans blue tissue extravasation that was significantly increased in VASP−/− animals compared to WT controls. In summary, we demonstrate here that endothelial VASP holds significant importance for endothelial barrier properties during hypoxia.

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Section: Discussionsupporting

confidence: 82%

Vasodilator Phosphostimulated Protein (VASP) Protects Endothelial Barrier Function During Hypoxia

et al. 2011

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“…Another mechanism contributing to reduced barrier function in VASP-defient endothelioma is impaired integrin-mediated adhesion to the extracellular matrix and reduced focal adhesion formation suggesting that VASP is not only important at cell-cell junctions to control barrier functionality (107). VASP depletion in HUVEC also aggravated thrombin-induced permeability and delayed reassembly of junctions during recovery (108). Interestingly, VASP expression is regulated by hypoxia-inducible factor (HIF1α) during hypoxia (109,110).…”

Section: Vasodilator-stimulated Phosphoprotein (Vasp)mentioning

confidence: 99%

The role of actin-binding proteins in the control of endothelial barrier integrity

García‐Ponce¹,

Citalán-Madrid²,

Velázquez-Avila³

et al. 2015

Thromb Haemost

117

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SummaryThe endothelial barrier of the vasculature is of utmost importance for separating the blood stream from underlying tissues. This barrier is formed by tight and adherens junctions (TJ and AJ) that form intercellular endothelial contacts. TJ and AJ are integral membrane structures that are connected to the actin cytoskeleton via various adaptor molecules. Consequently, the actin cytoskeleton plays a crucial role in regulating the stability of endothelial cell contacts and vascular permeability. While a circumferential cortical actin ring stabilises junctions, the formation of contractile stress fibres, e. g. under inflammatory conditions, can contribute to junction destabilisation. However, the role of actin-binding proteins (ABP) in the control of vascular permeability has long been underestimated. Naturally, ABP regulate permeability via regulation of actin remodelling but some actin-binding molecules can also act independently of actin and control vascular permeability via various signalling mechanisms such as activation of small GTPases. Several studies have recently been published highlighting the importance of actin-binding molecules such as cortactin, ezrin/ radixin/moesin, Arp2/3, VASP or WASP for the control of vascular permeability by various mechanisms. These proteins have been described to regulate vascular permeability under various pathophysiological conditions and are thus of clinical relevance as targets for the development of treatment strategies for disorders that are characterised by vascular hyperpermeability such as sepsis. This review highlights recent advances in determining the role of ABP in the control of endothelial cell contacts and vascular permeability.

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“…However, involvement of PAR-1 remains to be confirmed, as we cannot completely rule out the possibility of off-target effects of our PAR-1 siRNA mixture. Nevertheless, previous reports have demonstrated that the thrombin/PAR-1 pathway is involved in barrier homeostasis in endothelial cells 20 , 21 . Thus, it seems plausible that it might be involved in a variety of homeostatic processes.…”

Section: Discussionmentioning

confidence: 96%

Tranexamic acid blocks the thrombin-mediated delay of epidermal permeability barrier recovery induced by the cedar pollen allergen, Cry j1

Nakanishi

Kumamoto

Denda

2018

Sci Rep

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We previously demonstrated that Cry j1, the major pollen allergen of Cryptomeria japonica (Japanese cedar), transiently increases protease activity and intracellular Ca2+ concentration in cultured human keratinocytes, and delays recovery after stratum corneum barrier disruption in human skin ex vivo. Topical application of tranexamic acid or trypsin-type serine protease inhibitors accelerates barrier recovery. We hypothesized that tranexamic acid might prevent the transient protease activity increase and the barrier recovery delay induced by Cry j1. Here, we tested this hypothesis and examined the mechanism involved. In cultured human keratinocytes, knock-down of protease-activated receptor 1 (PAR-1) reduced the transient increase of calcium induced by Cry j1, whereas knock-down of PAR-2 did not. Knock-down of thrombin significantly reduced the transient increases of calcium concentration and protease activity. Tranexamic acid, soybean trypsin inhibitor, or bivalirudin (a thrombin inhibitor) also reduced the calcium elevation induced by Cry j1 and/or thrombin. Co-application of tranexamic acid or bivalirudin with Cry j1 to human skin ex vivo blocked the delay of barrier recovery. These results suggest that thrombin and PAR-1 or PAR-1-like receptor might mediate the adverse effects of Cry j1 on human epidermal keratinocytes, and could open up a new strategy for treating inflammatory skin diseases.

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Vasodilator‐stimulated phosphoprotein deficiency potentiates PAR‐1‐induced increase in endothelial permeability in mouse lungs

Cited by 7 publications

References 39 publications

Vasodilator Phosphostimulated Protein (VASP) Protects Endothelial Barrier Function During Hypoxia

Vasodilator Phosphostimulated Protein (VASP) Protects Endothelial Barrier Function During Hypoxia

The role of actin-binding proteins in the control of endothelial barrier integrity

Tranexamic acid blocks the thrombin-mediated delay of epidermal permeability barrier recovery induced by the cedar pollen allergen, Cry j1

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