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TMEM16E regulates endothelial cell procoagulant activity and thrombosis

Endothelial cells (ECs) normally form an anticoagulant surface under physiological conditions, but switch to support coagulation following pathogenic stimuli. This switch promotes thrombotic cardiovascular disease. To generate thrombin at physiologic rates, coagulation proteins assemble on a membran...

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Autores principales: Schmaier, Alec A., Anderson, Papa F., Chen, Siyu M., El-Darzi, Emale, Aivasovsky, Ivan, Kaushik, Milan P., Sack, Kelsey D., Hartzell, H. Criss, Parikh, Samir M., Flaumenhaft, Robert, Schulman, Sol
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10231993/
https://www.ncbi.nlm.nih.gov/pubmed/36951953
http://dx.doi.org/10.1172/JCI163808
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author Schmaier, Alec A.
Anderson, Papa F.
Chen, Siyu M.
El-Darzi, Emale
Aivasovsky, Ivan
Kaushik, Milan P.
Sack, Kelsey D.
Hartzell, H. Criss
Parikh, Samir M.
Flaumenhaft, Robert
Schulman, Sol
author_facet Schmaier, Alec A.
Anderson, Papa F.
Chen, Siyu M.
El-Darzi, Emale
Aivasovsky, Ivan
Kaushik, Milan P.
Sack, Kelsey D.
Hartzell, H. Criss
Parikh, Samir M.
Flaumenhaft, Robert
Schulman, Sol
author_sort Schmaier, Alec A.
collection PubMed
description Endothelial cells (ECs) normally form an anticoagulant surface under physiological conditions, but switch to support coagulation following pathogenic stimuli. This switch promotes thrombotic cardiovascular disease. To generate thrombin at physiologic rates, coagulation proteins assemble on a membrane containing anionic phospholipid, most notably phosphatidylserine (PS). PS can be rapidly externalized to the outer cell membrane leaflet by phospholipid “scramblases,” such as TMEM16F. TMEM16F-dependent PS externalization is well characterized in platelets. In contrast, how ECs externalize phospholipids to support coagulation is not understood. We employed a focused genetic screen to evaluate the contribution of transmembrane phospholipid transport on EC procoagulant activity. We identified 2 TMEM16 family members, TMEM16F and its closest paralog, TMEM16E, which were both required to support coagulation on ECs via PS externalization. Applying an intravital laser-injury model of thrombosis, we observed, unexpectedly, that PS externalization was concentrated at the vessel wall, not on platelets. TMEM16E-null mice demonstrated reduced vessel-wall–dependent fibrin formation. The TMEM16 inhibitor benzbromarone prevented PS externalization and EC procoagulant activity and protected mice from thrombosis without increasing bleeding following tail transection. These findings indicate the activated endothelial surface is a source of procoagulant phospholipid contributing to thrombus formation. TMEM16 phospholipid scramblases may be a therapeutic target for thrombotic cardiovascular disease.
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spelling pubmed-102319932023-06-01 TMEM16E regulates endothelial cell procoagulant activity and thrombosis Schmaier, Alec A. Anderson, Papa F. Chen, Siyu M. El-Darzi, Emale Aivasovsky, Ivan Kaushik, Milan P. Sack, Kelsey D. Hartzell, H. Criss Parikh, Samir M. Flaumenhaft, Robert Schulman, Sol J Clin Invest Research Article Endothelial cells (ECs) normally form an anticoagulant surface under physiological conditions, but switch to support coagulation following pathogenic stimuli. This switch promotes thrombotic cardiovascular disease. To generate thrombin at physiologic rates, coagulation proteins assemble on a membrane containing anionic phospholipid, most notably phosphatidylserine (PS). PS can be rapidly externalized to the outer cell membrane leaflet by phospholipid “scramblases,” such as TMEM16F. TMEM16F-dependent PS externalization is well characterized in platelets. In contrast, how ECs externalize phospholipids to support coagulation is not understood. We employed a focused genetic screen to evaluate the contribution of transmembrane phospholipid transport on EC procoagulant activity. We identified 2 TMEM16 family members, TMEM16F and its closest paralog, TMEM16E, which were both required to support coagulation on ECs via PS externalization. Applying an intravital laser-injury model of thrombosis, we observed, unexpectedly, that PS externalization was concentrated at the vessel wall, not on platelets. TMEM16E-null mice demonstrated reduced vessel-wall–dependent fibrin formation. The TMEM16 inhibitor benzbromarone prevented PS externalization and EC procoagulant activity and protected mice from thrombosis without increasing bleeding following tail transection. These findings indicate the activated endothelial surface is a source of procoagulant phospholipid contributing to thrombus formation. TMEM16 phospholipid scramblases may be a therapeutic target for thrombotic cardiovascular disease. American Society for Clinical Investigation 2023-06-01 /pmc/articles/PMC10231993/ /pubmed/36951953 http://dx.doi.org/10.1172/JCI163808 Text en © 2023 Schmaier et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Schmaier, Alec A.
Anderson, Papa F.
Chen, Siyu M.
El-Darzi, Emale
Aivasovsky, Ivan
Kaushik, Milan P.
Sack, Kelsey D.
Hartzell, H. Criss
Parikh, Samir M.
Flaumenhaft, Robert
Schulman, Sol
TMEM16E regulates endothelial cell procoagulant activity and thrombosis
title TMEM16E regulates endothelial cell procoagulant activity and thrombosis
title_full TMEM16E regulates endothelial cell procoagulant activity and thrombosis
title_fullStr TMEM16E regulates endothelial cell procoagulant activity and thrombosis
title_full_unstemmed TMEM16E regulates endothelial cell procoagulant activity and thrombosis
title_short TMEM16E regulates endothelial cell procoagulant activity and thrombosis
title_sort tmem16e regulates endothelial cell procoagulant activity and thrombosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10231993/
https://www.ncbi.nlm.nih.gov/pubmed/36951953
http://dx.doi.org/10.1172/JCI163808
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