Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms
As blood transitions from steady laminar flow (S-flow) in healthy arteries to disturbed flow (D-flow) in aneurysmal arteries, platelets are subjected to external forces. Biomechanical platelet activation is incompletely understood and is a potential mechanism behind antiplatelet medication resistanc...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2022-05-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI152373 |
| _version_ | 1811329281453719552 |
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| author | Craig N. Morrell Doran Mix Anu Aggarwal Rohan Bhandari Matthew Godwin Phillip Owens III Sean P. Lyden Adam Doyle Krystin Krauel Matthew T. Rondina Amy Mohan Charles J. Lowenstein Sharon Shim Shaun Stauffer Vara Prasad Josyula Sara K. Ture David I. Yule Larry E. Wagner III John M. Ashton Ayman Elbadawi Scott J. Cameron |
| author_facet | Craig N. Morrell Doran Mix Anu Aggarwal Rohan Bhandari Matthew Godwin Phillip Owens III Sean P. Lyden Adam Doyle Krystin Krauel Matthew T. Rondina Amy Mohan Charles J. Lowenstein Sharon Shim Shaun Stauffer Vara Prasad Josyula Sara K. Ture David I. Yule Larry E. Wagner III John M. Ashton Ayman Elbadawi Scott J. Cameron |
| author_sort | Craig N. Morrell |
| collection | DOAJ |
| description | As blood transitions from steady laminar flow (S-flow) in healthy arteries to disturbed flow (D-flow) in aneurysmal arteries, platelets are subjected to external forces. Biomechanical platelet activation is incompletely understood and is a potential mechanism behind antiplatelet medication resistance. Although it has been demonstrated that antiplatelet drugs suppress the growth of abdominal aortic aneurysms (AAA) in patients, we found that a certain degree of platelet reactivity persisted in spite of aspirin therapy, urging us to consider additional antiplatelet therapeutic targets. Transcriptomic profiling of platelets from patients with AAA revealed upregulation of a signal transduction pathway common to olfactory receptors, and this was explored as a mediator of AAA progression. Healthy platelets subjected to D-flow ex vivo, platelets from patients with AAA, and platelets in murine models of AAA demonstrated increased membrane olfactory receptor 2L13 (OR2L13) expression. A drug screen identified a molecule activating platelet OR2L13, which limited both biochemical and biomechanical platelet activation as well as AAA growth. This observation was further supported by selective deletion of the OR2L13 ortholog in a murine model of AAA that accelerated aortic aneurysm growth and rupture. These studies revealed that olfactory receptors regulate platelet activation in AAA and aneurysmal progression through platelet-derived mediators of aortic remodeling. |
| first_indexed | 2024-04-13T15:41:02Z |
| format | Article |
| id | doaj.art-a9f8b471213f415ebf2719e112f1c1ce |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-04-13T15:41:02Z |
| publishDate | 2022-05-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-a9f8b471213f415ebf2719e112f1c1ce2022-12-22T02:41:08ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-05-011329Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysmsCraig N. MorrellDoran MixAnu AggarwalRohan BhandariMatthew GodwinPhillip Owens IIISean P. LydenAdam DoyleKrystin KrauelMatthew T. RondinaAmy MohanCharles J. LowensteinSharon ShimShaun StaufferVara Prasad JosyulaSara K. TureDavid I. YuleLarry E. Wagner IIIJohn M. AshtonAyman ElbadawiScott J. CameronAs blood transitions from steady laminar flow (S-flow) in healthy arteries to disturbed flow (D-flow) in aneurysmal arteries, platelets are subjected to external forces. Biomechanical platelet activation is incompletely understood and is a potential mechanism behind antiplatelet medication resistance. Although it has been demonstrated that antiplatelet drugs suppress the growth of abdominal aortic aneurysms (AAA) in patients, we found that a certain degree of platelet reactivity persisted in spite of aspirin therapy, urging us to consider additional antiplatelet therapeutic targets. Transcriptomic profiling of platelets from patients with AAA revealed upregulation of a signal transduction pathway common to olfactory receptors, and this was explored as a mediator of AAA progression. Healthy platelets subjected to D-flow ex vivo, platelets from patients with AAA, and platelets in murine models of AAA demonstrated increased membrane olfactory receptor 2L13 (OR2L13) expression. A drug screen identified a molecule activating platelet OR2L13, which limited both biochemical and biomechanical platelet activation as well as AAA growth. This observation was further supported by selective deletion of the OR2L13 ortholog in a murine model of AAA that accelerated aortic aneurysm growth and rupture. These studies revealed that olfactory receptors regulate platelet activation in AAA and aneurysmal progression through platelet-derived mediators of aortic remodeling.https://doi.org/10.1172/JCI152373Vascular biology |
| spellingShingle | Craig N. Morrell Doran Mix Anu Aggarwal Rohan Bhandari Matthew Godwin Phillip Owens III Sean P. Lyden Adam Doyle Krystin Krauel Matthew T. Rondina Amy Mohan Charles J. Lowenstein Sharon Shim Shaun Stauffer Vara Prasad Josyula Sara K. Ture David I. Yule Larry E. Wagner III John M. Ashton Ayman Elbadawi Scott J. Cameron Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms The Journal of Clinical Investigation Vascular biology |
| title | Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms |
| title_full | Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms |
| title_fullStr | Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms |
| title_full_unstemmed | Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms |
| title_short | Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms |
| title_sort | platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms |
| topic | Vascular biology |
| url | https://doi.org/10.1172/JCI152373 |
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