Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms

• Published in: The Journal of clinical investigation Vol. 132; no. 9; pp. 1 - 16
• Main Authors: Morrell, Craig N, Mix, Doran, Aggarwal, Anu, Bhandari, Rohan, Godwin, Matthew, Owens, 3rd, Phillip, Lyden, Sean P, Doyle, Adam, Krauel, Krystin, Rondina, Matthew T, Mohan, Amy, Lowenstein, Charles J, Shim, Sharon, Stauffer, Shaun, Josyula, Vara Prasad, Ture, Sara K, Yule, David I, Wagner, 3rd, Larry E, Ashton, John M, Elbadawi, Ayman, Cameron, Scott J
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-05-2022
• Subjects: Activation; Animal models; Animals; Aortic Aneurysm - genetics; Aortic Aneurysm - metabolism; Aortic Aneurysm, Abdominal - genetics; Aortic aneurysms; Arteries; Aspirin; Biomechanics; Biomedical research; Blood clots; Blood platelets; Blood Platelets - metabolism; Cardiovascular research; Cellular signal transduction; Coronary vessels; Development and progression; Disease Models, Animal; Drug development; Drug resistance; Drug screening; Drug therapy; Health aspects; Humans; Ligands; Mice; Odorant receptors; Olfactory receptors; Physiological aspects; Platelet Activation; Platelet Aggregation Inhibitors - therapeutic use; Platelets; Protein expression; Proteins; Receptor mechanisms; Receptors, Odorant - genetics; Signal transduction; Therapeutic targets; Transcriptomics; Vascular biology; Veins & arteries; United States; Signal transduction; Platelets; Thrombosis; Vascular Biology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI152373

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.