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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Clinical Investigation
2023
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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. |
format | Online Article Text |
id | pubmed-10231993 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Clinical Investigation |
record_format | MEDLINE/PubMed |
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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