G protein–dependent basal and evoked endothelial cell vWF secretion

Rusu, Luiza; Андреева, А. В.; Visintine, David J.; Vogel, Stephen M.; Stojanovic‐Terpo, Aleksandra; Chernaya, Olga; Liu, Guoquan; Bakhshi, Farnaz R.; Haberichter, Sandra L.; Iwanari, Hiroko; Kusano-Arai, Osamu; Suzuki, Naomichi; Hamakubo, Takao; Kozasa, Tohru; Cho, Jaehyung; Du, Xiaoping; Minshall, Richard D.

doi:10.1182/blood-2013-03-489351

Cited by 26 publications

(33 citation statements)

References 44 publications

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“…Rusu et al have previously demonstrated that the interaction between soluble N‐ethylmaleimide sensitive factor‐attachment protein alpha (αSNAP) and guanine nucleotide‐binding alpha‐subunit 12 (Gα12) is necessary for both the basal and thrombin‐induced secretion of vWF from endothelial cells. Recently, Rusu et al have reported that, through the generation of an inhibitory peptide targeted against αSNAP, the direct interaction between αSNAP and Gα12 could be hindered .…”

Section: Systemic Role Of Vwf In Coagulopathy and Inflammation Followmentioning

confidence: 99%

“…By preventing this interaction, the researchers demonstrated decreased membrane fusion events of WPBs and, therefore, less vWF secretion. When the inhibitory peptide was tested in mice that had undergone a cecal ligation and puncture (CLP) to induce sepsis, there were both reduced plasma vWF levels and markers of microvascular thrombosis of the kidney . Furthermore, it was found that while all wild‐type mice had died by 96 hours in the CLP model, homozygous Gα12 knockouts demonstrated reduced vWF levels and 100% survival.…”

Section: Systemic Role Of Vwf In Coagulopathy and Inflammation Followmentioning

confidence: 99%

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Von Willebrand factor as a thrombotic and inflammatory mediator in critical illness

et al. 2020

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The endothelial exocytosis of high‐molecular‐weight multimeric von Willebrand factor (vWF) may occur in critical illness states, including trauma and sepsis, leading to the sustained elevation and altered composition of plasma vWF. These critical illnesses involve the common process of sympathoadrenal activation and loss of the endothelial glycocalyx. As a prothrombotic and proinflammatory molecule that interacts with the endothelium, the alterations exhibited by vWF in critical illness have been implicated in the development and damaging effects of downstream pathologies, such as disseminated intravascular coagulation and systemic inflammatory response syndrome. Given the role of vWF in these pathologies, there has been a recent push to further understand how the molecule may be involved in the pathophysiology of related diseases, such as trauma‐induced coagulopathy and acute renal injury, which are also known to develop secondarily to critical illness states. Elucidation of the role of vWF across the broader spectrum of generalized pathologies may provide a basis for the development of novel preventative and restorative measures, while also bolstering the scaffold of more widely used treatments, such as the administration of plasma‐containing blood products.

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Section: Systemic Role Of Vwf In Coagulopathy and Inflammation Followmentioning

confidence: 99%

Section: Systemic Role Of Vwf In Coagulopathy and Inflammation Followmentioning

confidence: 99%

Von Willebrand factor as a thrombotic and inflammatory mediator in critical illness

et al. 2020

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“…Although the storage of VWF in WPB of endothelial cells has been known for decades, the molecular mechanisms governing WPB docking with plasma membrane and VWF secretion remained poorly understood. Using a combination of pharmacological, genetic, and molecular techniques, Rusu et al dissected a mechanism for VWF secretion from endothelial cells mediated via Gαq/11 and Gα12 that can be triggered during basal or stimulated conditions [41]. In addition, Bierings et al reported the Rab27A effector synaptotagmin-like protein 4-a (Slp4-a) plays a critical role in regulating hormone-evoked WPB exocytosis [42].…”

Section: Regulation Of Vwf Protein Secretionmentioning

confidence: 99%

Regulation of VWF expression, and secretion in health and disease

Xiang

Hwa

2016

Current Opinion in Hematology

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PURPOSE OF REVIEW VWF is a large multi-domain, multimeric glycoprotein that plays an essential role in regulating the balance between blood clotting and bleeding. Aberrant VWF regulation can lead to a spectrum of diseases extending from bleeding disorders (VWD) to aberrant thrombosis (TTP). Understanding the biology of VWF expression and secretion is essential for developing novel targeted therapies for VWF related hemostasis disorders. RECENT FINDINGS A number of recent elegant in vitro and in vivo studies will be highlighted including the discovery of intronic splicing in the VWF gene, miRNA regulated VWF gene expression, and syntaxin binding protein and autophagy mediated VWF secretion. Compared with the already established critical role of VWF in VWD and TTP pathophysiology, additional clinical studies have clarified and reinforced the association of increased plasma levels of VWF with an increased risk of stroke, myocardial infarction, venous thrombosis and diabetic thrombotic complications. Moreover, experimental mouse models of ischaemic stroke and myocardial infarction have further support VWF as a potential therapeutic target. SUMMARY VWF biosynthesis, maturation, and secretion is a complex process, which mandates tight regulation. Significant progress has been made in our understandings of VWF expression and secretion and its association with thrombotic diseases, contributing to the development of novel targeting VWF drugs for prevention and treatment of deficient and enhanced hemostasis.

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“…Among these, the implication of a series of intracellular proteins (including but not limited to: RalA, Rab3, Rab27a, Rab15, Rab33a, Rab37, Munc13-4, Munc18c, Slp4a, Annexin A2-S100A10, syntaxin-binding protein 1, syntaxin-4, VAMP-3, G proteins) has been documented based on the finding that deletion or mutation of these proteins modulates constitutive and/or regulated release of VWF. 44,[65][66][67][68][69][70][71][72][73] Recently, an unexpected and novel type of regulation of VWF release has been reported by Torisu and colleagues. 74 Not only did they observe that WPBs are often in close proximity of autophagosomes but they also detected the presence of VWF in these organelles.…”

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confidence: 99%

von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

Lenting

Olivier

Denis

2015

Blood

344

336

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To understand the placement of a certain protein in a physiological system and the pathogenesis of related disorders, it is not only of interest to determine its function but also important to describe the sequential steps in its life cycle, from synthesis to secretion and ultimately its clearance. von Willebrand factor (VWF) is a particularly intriguing case in this regard because of its important auxiliary roles (both intra-and extracellular) that implicate a wide range of other proteins: its presence is required for the formation and regulated release of endothelial storage organelles, the Weibel-Palade bodies (WPBs), whereas VWF is also a key determinant in the clearance of coagulation factor VIII. Thus, understanding the molecular and cellular basis of the VWF life cycle will help us gain insight into the pathogenesis of von Willebrand disease, design alternative treatment options to prolong the factor VIII half-life, and delineate the role of VWF and coresidents of the WPBs in the prothrombotic and proinflammatory response of endothelial cells. In this review, an update on our current knowledge on VWF biosynthesis, secretion, and clearance is provided and we will discuss how they can be affected by the presence of protein defects. (Blood. 2015;125(13): 2019-2028 Introduction von Willebrand (VW) factor (VWF) is a multimeric glycoprotein present in blood plasma, the subendothelial matrix, as well as storage granules in endothelial cells (Weibel-Palade [WP] bodies [WPBs]) and platelets (a-granules).1 Although a series of novel functional properties of VWF has recently been proposed, 2 the protein is mostly known for its contribution to the hemostatic process: it mediates platelet adhesion and aggregation at sites of vascular injury and carries coagulation factor VIII (FVIII) in the circulation. 1 Patients lacking VWF manifest a severe hemorrhagic phenotype, originating from defective formation of platelet-rich thrombi and a secondary deficiency of FVIII impairing the generation of a fibrin network. Functional and/or quantitative deficiencies of VWF are known as von Willebrand disease (VWD), a disorder affecting 0.01% to 1% of the population. 3 Quantitative deficiencies of VWF result from changes in biosynthesis, secretion, and/or clearance of the protein. In this review, we will provide an overview of the current knowledge on each of these processes and we will discuss how they can be affected by the presence of protein defects. Part I: Basics of VWF biosynthesisPrimary structure VWF is produced in endothelial cells and megakaryocytes as a single prepropolypeptide of 2813 aa. The primary sequence of VWF was reported in 1986, and rapidly the presence of repeating domain structures within the protein was recognized. 4 The different domains are arranged in the order: D1-D2-D9-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2-CK, with the D1-D2 domains representing the propeptide and the remainder corresponding to the mature VWF subunit (Figure 1). [4][5][6] Progress in structural and bioinformatical analysis of protein structures...

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G protein–dependent basal and evoked endothelial cell vWF secretion

Abstract: Key Points Gα12 interaction with α-SNAP regulates basal EC vWF secretion. PAR-1 activation-dependent signaling via Gα12/RhoA and Gαq/11 enhances vWF secretion.

Cited by 26 publications

References 44 publications

Von Willebrand factor as a thrombotic and inflammatory mediator in critical illness

Von Willebrand factor as a thrombotic and inflammatory mediator in critical illness

Regulation of VWF expression, and secretion in health and disease

von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends

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