{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T17:26:16Z","timestamp":1793985976492,"version":"4.8.0"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"15","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1HL131872"],"award-info":[{"award-number":["RO1HL131872"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL131872-S1"],"award-info":[{"award-number":["R01HL131872-S1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32HL007915"],"award-info":[{"award-number":["T32HL007915"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U54HL165442"],"award-info":[{"award-number":["U54HL165442"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association Established Investigator Award","doi-asserted-by":"publisher","award":["960273"],"award-info":[{"award-number":["960273"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"name":"American Heart Association Protein Binding Atlas Pilot Project","award":["25PBA1513942"],"award-info":[{"award-number":["25PBA1513942"]}],"id":[{"id":"https:\/\/ror.org\/013kjyp64","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Erin Beatty Fund"},{"DOI":"10.13039\/100006458","name":"Children\u2019s Hospital of Philadelphia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006458","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Kibel Fund"},{"name":"Valley Hospital Foundation \u2018Marjorie C. Bunnel\u2019 charitable fund"},{"name":"The William J. Rashkind Endowment","id":[{"id":"https:\/\/ror.org\/0229evh14","id-type":"ROR","asserted-by":"crossref"}]},{"name":"The Children\u2019s Hospital of Philadelphia Cardiac Center Innovation Grant","id":[{"id":"https:\/\/ror.org\/01z7r7q48","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,11,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Mitral regurgitation (MR) pathophysiology involves increased serotonin (5-HT) receptor (HTR) expression and signalling, together with reduced 5-HT transporter (SLC6A4) expression in mitral valve interstitial cells (MVIC). The mechanosensitive calcium channels, PIEZO1 and PIEZO2, regulate cellular responses to a variety of mechanical conditions; however, PIEZO1 and PIEZO2 have not been studied in MR. We investigated the hypothesis that PIEZO1 and PIEZO2 mediate, through 5-HT mechanisms, both homeostasis in normal mitral valves (nMV) and in the pathophysiology of MR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Immunofluorescence and Western blots demonstrated the presence of PIEZO1 and PIEZO2 in samples of explanted human nMV and MR. MVIC derived from nMV and MR leaflets also expressed PIEZO1 and PIEZO2. Single-cell RNA sequencing (scRNA-seq) analyses of nMV and MR leaflet samples from 9 MR and 5 nMV cases identified seven cell types: endothelial cells, smooth muscle cells, T cells, macrophages, and three distinct MVIC phenotypes, VIC1, VIC2, and VIC3. MVIC together comprised 97% of all valve cells, irrespective of valve pathology. In addition, scRNA-seq of nMV and MR leaflets demonstrated MVIC PIEZO1 and PIEZO2 expression, together with HTR2B and SLC6A4. MVIC cultures, with no added 5-HT, demonstrated that PIEZO1 activation with its agonist, Yoda1, increased MVIC Ca2+ uptake. This was inhibited by PIEZO1-siRNA, and Dooku1, a Yoda1 antagonist, but not PIEZO2-siRNA or noncoding RNA. Additional MVIC studies revealed that in static MVIC cultures, PIEZO1 activation with Yoda1 downregulated SLC6A4, upregulated HTR2B, and increased 5-HT levels and protein synthesis. Cyclic tension MVIC bioreactor studies showed that either PIEZO1-siRNA or PIEZO2-siRNA mitigated tension-induced SLC6A4 downregulation and increased collagen synthesis; only PIEZO2-siRNA mitigated both static and cyclic tension-induced MVIC 5-HT production.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings have identified a novel link between mechanotransduction, 5-HT production and receptor signalling, and collagen synthesis, suggesting PIEZO1, PIEZO2, and downstream 5-HT pathways as potential therapeutic targets for mitigating MR progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvag190","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T08:14:02Z","timestamp":1788423242000},"page":"2222-2238","source":"Crossref","is-referenced-by-count":0,"title":["Mechanosensing channels PIEZO1 and PIEZO2 regulate mitral valve serotonin-mediated homeostasis and pathophysiology"],"prefix":"10.1093","volume":"122","author":[{"given":"Stanley J","family":"Stachelek","sequence":"first","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily J","family":"Hauber","sequence":"additional","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqiu","family":"Yang","sequence":"additional","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devin W","family":"Laurence","sequence":"additional","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7215-1452","authenticated-orcid":false,"given":"Vitali","family":"Rusinkevich","sequence":"additional","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiran","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estibaliz","family":"Castillero","sequence":"additional","affiliation":[{"name":"Department of Surgery, Columbia University , New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin B","family":"Pressly","sequence":"additional","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Brady","sequence":"additional","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikia T","family":"Toomey","sequence":"additional","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilia","family":"Fishbein","sequence":"additional","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Martinez","sequence":"additional","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza Mohammad","family":"Karim","sequence":"additional","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ephraim","family":"Jacobson","sequence":"additional","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1675-0116","authenticated-orcid":false,"given":"Dov","family":"Levine","sequence":"additional","affiliation":[{"name":"Department of Surgery, Columbia University , New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawnaleh","family":"Cada","sequence":"additional","affiliation":[{"name":"The Cardiac Center, The Children\u2019s Hospital of Philadelphia , Philadelphia, PA 19104 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