Membrane-anchored proteases in endothelial cell biology

Antalis, Toni M.; Conway, Gregory D.; Peroutka, Raymond J.; Buzza, Marguerite S.

doi:10.1097/moh.0000000000000238

Cited by 19 publications

(14 citation statements)

References 100 publications

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“…14,15 It is well known that membrane anchored proteases are important in regulating endothelial cellular biology. 16 In this regard, TXA is a nonspecific serine protease inhibitor and its clinical effects may not be limited to inhibiting fibrinolysis.…”

Section: Discussionmentioning

confidence: 99%

The effect of tranexamic acid dosing regimen on trauma/hemorrhagic shock-related glycocalyx degradation and endothelial barrier permeability: An in vitro model

Carge

Diebel²,

Liberati³

2022

J Trauma Acute Care Surg

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BACKGROUND: Improved outcomes with early tranexamic acid (TXA) following trauma hemorrhagic shock (T/HS) may be related to its antifibrinolytic, as well as anti-inflammatory properties. Previous in vitro studies have shown that early TXA administration protects against T/HS endothelial barrier dysfunction and associated glycocalyx degradation. An intact endothelial glycocalyx may protect against subsequent neutrophil mediated tissue injury. We postulated that early TXA administration would mitigate against glycocalyx damage and resultant neutrophil adherence and transmigration through the endothelial barrier. This was studied in vitro using a microfluidic flow platform. METHODS:Human umbilical vein endothelial cell monolayers were subjected to control or shock conditions (hypoxia + epinephrine) followed by administration of TXA 90 minutes or 180 minutes later. RESULTS:"Early" TXA administration protected against glycocalyx degradation, biomarkers of increased permeability and the development of a fibrinolytic phenotype. This was associated with decreased neutrophil endothelial adherence and transmigration. There were no differences in low versus high TXA concentrations. The protective effects were only significant with "early" TXA administration. CONCLUSION: There was a concentration and temporal effect of TXA administration on endothelial glycocalyx degradation. This was associated with "vascular leakiness" as indexed by the relative ratio of Ang-2/1 and polymorphonuclear neutrophil transmigration. Tranexamic acid if administered in patients with T/HS should be administered "early"; this includes in the prehospital setting.

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Section: Discussionmentioning

confidence: 99%

The effect of tranexamic acid dosing regimen on trauma/hemorrhagic shock-related glycocalyx degradation and endothelial barrier permeability: An in vitro model

Carge

Diebel²,

Liberati³

2022

J Trauma Acute Care Surg

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“…1; refs. 19,20,[22][23][24]. The manner in which they are linked to the cell surface may be through type I or type II singlepass transmembrane domains or linked via glycophosphatidylinositol (GPI)-anchors.…”

Section: Membrane-anchored Serine Proteasesmentioning

confidence: 99%

Membrane-Anchored Serine Proteases and Protease-Activated Receptor-2–Mediated Signaling: Co-Conspirators in Cancer Progression

2019

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Pericellular proteolysis provides a significant advantage to developing tumors through the ability to remodel the extracellular matrix, promote cell invasion and migration, and facilitate angiogenesis. Recent advances demonstrate that pericellular proteases can also communicate directly to cells by activation of a unique group of transmembrane G-protein-coupled receptors (GPCR) known as proteaseactivated receptors (PAR). In this review, we discuss the specific roles of one of four mammalian PARs, namely PAR-2, which is overexpressed in advanced stage tumors and is activated by trypsin-like serine proteases that are highly expressed or otherwise dysregulated in many cancers. We highlight recent insights into the ability of different protease agonists to bias PAR-2 signaling and the newly emerging evidence for an interplay between PAR-2 and membrane-anchored serine proteases, which may co-conspire to promote tumor progression and metastasis. Interfering with these pathways might provide unique opportunities for the development of new mechanism-based strategies for the treatment of advanced and metastatic cancers.

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“…The glioma cells are not the only source of proteases in the tumor. In fact, endothelial cells in glioblastomas are responsible for a substantial proportion of the extracellular matrix‐degrading proteolytic activity within the glioma microenvironment (Antalis, Conway, Peroutka, & Buzza, ; Lakka, Gondi, & Rao, ). In addition to endothelial cells, stem cells and others, glioma‐infiltrating microglial cells (GIMs) are a prominent part of gliomas (Charles et al, ).…”

Section: Modulation Of Brain Extracellular Matrix By Proteases and Glmentioning

confidence: 99%

Glioma infiltration and extracellular matrix: key players and modulators

Ferrer

Moura‐Neto

Mentlein

2018

Glia

147

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An outstanding characteristic of gliomas is their infiltration into brain parenchyma, a property that impairs complete surgical resection; consequently, these tumors might recur, resulting in a high mortality rate. Gliomas invade along preferential routes, such as those along white matter tracts and in the perineuronal and perivascular spaces. Brain extracellular components and their partners and modulators play a crucial role in glioma cell invasion. This review presents an extensive survey of the literature, showing how the brain extracellular matrix (ECM) is modulated during the glioma infiltration process. We explore aspects of ECM interaction with glioma cells, reviewing the main glycosaminoglycans, glycoproteins and proteoglycans. We discuss the roles of ECM-binding proteins, including CD44, RHAMM, integrins and axonal guidance molecules, and highlight the role of proteases and glycosidases in glioma infiltration; in binding and release chemokines, cytokines and growth factors; and in generating new bioactive ECM fragments. We also consider the roles of cytoskeletal signaling, angiogenesis, miRNAs and the glial-to-mesenchymal transition linked to glioma invasion. We closely discuss therapeutic approaches based on the modulation of the extracellular matrix, targeting the control of glioma infiltration, its relative failure in clinical trials, and potential means to overcome this difficulty.

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Membrane-anchored proteases in endothelial cell biology

Cited by 19 publications

References 100 publications

The effect of tranexamic acid dosing regimen on trauma/hemorrhagic shock-related glycocalyx degradation and endothelial barrier permeability: An in vitro model

The effect of tranexamic acid dosing regimen on trauma/hemorrhagic shock-related glycocalyx degradation and endothelial barrier permeability: An in vitro model

Membrane-Anchored Serine Proteases and Protease-Activated Receptor-2–Mediated Signaling: Co-Conspirators in Cancer Progression

Glioma infiltration and extracellular matrix: key players and modulators

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