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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2023-06-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI163808 |
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| author | Alec A. Schmaier Papa F. Anderson Siyu M. Chen Emale El-Darzi Ivan Aivasovsky Milan P. Kaushik Kelsey D. Sack H. Criss Hartzell Samir M. Parikh Robert Flaumenhaft Sol Schulman |
| author_facet | Alec A. Schmaier Papa F. Anderson Siyu M. Chen Emale El-Darzi Ivan Aivasovsky Milan P. Kaushik Kelsey D. Sack H. Criss Hartzell Samir M. Parikh Robert Flaumenhaft Sol Schulman |
| author_sort | Alec A. Schmaier |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T12:09:00Z |
| format | Article |
| id | doaj.art-9e71fa5130a2448fa08eb8ede82391f7 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:00Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-9e71fa5130a2448fa08eb8ede82391f72023-11-07T16:20:25ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-06-0113311TMEM16E regulates endothelial cell procoagulant activity and thrombosisAlec A. SchmaierPapa F. AndersonSiyu M. ChenEmale El-DarziIvan AivasovskyMilan P. KaushikKelsey D. SackH. Criss HartzellSamir M. ParikhRobert FlaumenhaftSol SchulmanEndothelial 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.https://doi.org/10.1172/JCI163808HematologyVascular biology |
| spellingShingle | Alec A. Schmaier Papa F. Anderson Siyu M. Chen Emale El-Darzi Ivan Aivasovsky Milan P. Kaushik Kelsey D. Sack H. Criss Hartzell Samir M. Parikh Robert Flaumenhaft Sol Schulman TMEM16E regulates endothelial cell procoagulant activity and thrombosis The Journal of Clinical Investigation Hematology Vascular biology |
| 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 | Hematology Vascular biology |
| url | https://doi.org/10.1172/JCI163808 |
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