Tissue Factor Prothrombotic Activity Is Regulated by Integrin-arf6 Trafficking

Arteriosclerosis, Thrombosis, and Vascular Biology
Andrea S RothmeierWolfram Ruf

Abstract

Coagulation initiation by tissue factor (TF) is regulated by cellular inhibitors, cell surface availability of procoagulant phosphatidylserine, and thiol-disulfide exchange. How these mechanisms contribute to keeping TF in a noncoagulant state and to generating prothrombotic TF remain incompletely understood. Here, we study the activation of TF in primary macrophages by a combination of pharmacological, genetic, and biochemical approaches. We demonstrate that primed macrophages effectively control TF cell surface activity by receptor internalization. After cell injury, ATP signals through the purinergic receptor P2rx7 induce release of TF+ microvesicles. TF cell surface availability for release onto microvesicles is regulated by the GTPase arf6 associated with integrin α4β1. Furthermore, microvesicles proteome analysis identifies activation of Gαi2 as a participating factor in the release of microvesicles with prothrombotic activity in flowing blood. ATP not only prevents TF and phosphatidylserine internalization but also induces TF conversion to a conformation with high affinity for its ligand, coagulation factor VII. Although inhibition of dynamin-dependent internalization also exposes outer membrane procoagulant phosphatidyl...Continue Reading

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Citations

Feb 22, 2018·Current Opinion in Cardiology·Joshua D Hutcheson, Elena Aikawa
Jul 22, 2018·Journal of Thrombosis and Haemostasis : JTH·H ZelayaW Ruf
Sep 26, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Megan A Slack, Scott M Gordon
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Sep 14, 2018·Seminars in Immunopathology·Michael W Graner
May 21, 2020·Annals of Hematology·Katharina HolsteinFlorian Langer
Oct 26, 2018·Arteriosclerosis, Thrombosis, and Vascular Biology·Hong S LuAlan Daugherty
Jan 13, 2021·International Journal of Molecular Sciences·Valeria Di BattistaAlessandro Lucchesi
Mar 13, 2021·Science·Nadine Müller-CallejaWolfram Ruf
Apr 25, 2021·Journal of Thrombosis and Thrombolysis·Wolfram Ruf
Apr 9, 2021·Journal of Thrombosis and Haemostasis : JTH·Piyushkumar R KapoparaEdward M Conway

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