{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:29:13Z","timestamp":1790393353848,"version":"4.1.0"},"posted":{"date-parts":[[2026,6,11]]},"group-title":"Physiology","reference-count":39,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Myogenic tone is a fundamental property of resistance arteries that stabilizes tissue perfusion by coupling intraluminal pressure to smooth muscle cell (SMC) depolarization, Ca\n                    <jats:sup>2+<\/jats:sup>\n                    influx, and vasoconstriction. TRPM4 (transient receptor potential melastatin 4) cation channels are required for this response in cerebral arteries, but whether TRPM4-dependent mechanotransduction is conserved across the broader resistance vasculature has remained unknown.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We combined droplet digital PCR, a newly generated\n                    <jats:italic>Trpm4<\/jats:italic>\n                    -Cre transgenic reporter mouse line, native-cell patch-clamp electrophysiology, pressure myography, selective pharmacological inhibition, and novel SMC-specific\n                    <jats:italic>Trpm4<\/jats:italic>\n                    -knockout (\n                    <jats:italic>Trpm4<\/jats:italic>\n                    -smKO) mice to define the expression, regulation, and functional importance of TRPM4 in cerebral, mesenteric, and skeletal muscle resistance arteries.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Trpm4<\/jats:italic>\n                    transcripts were detected in all three vascular beds, and genetic reporter-based mapping localized TRPM4 expression to SMCs in multiple organs. Using conventional whole-cell patch-clamp electrophysiology, we recorded cation currents activated by high intracellular [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ] and sensitive to the selective TRPM4 blocker 4-chloro-2-(1-naphthyloxyacetamido) benzoic acid (NBA) in native SMCs from all three beds. In cells patch-clamped using the amphotericin B-perforated configuration, stretching the plasma membrane by applying negative pressure (-20 mmHg) through the patch pipette activated transient inward cation currents that were suppressed by NBA. The selective angiotensin II type 1 receptor (AT\n                    <jats:sub>1<\/jats:sub>\n                    R) blocker losartan also inhibited stretch-induced currents without affecting Ca\n                    <jats:sup>2+<\/jats:sup>\n                    -activated whole-cell TRPM4 currents, indicating that AT\n                    <jats:sub>1<\/jats:sub>\n                    R signaling is required for mechanotransduction in SMCs from all three vascular beds. In pressurized arteries with established myogenic tone, NBA produced reversible, concentration-dependent suppression of pressure-induced constriction of cerebral, mesenteric, and skeletal muscle arteries while sparing constriction induced by direct depolarization of SMCs with high (60 mM) extracellular [K\n                    <jats:sup>+<\/jats:sup>\n                    ]. TRPM4-dependent whole-cell currents and stretch-induced cation currents were decreased in SMCs from\n                    <jats:italic>Trpm4<\/jats:italic>\n                    -smKO mice, and myogenic tone was essentially absent in all three vascular beds from these animals.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings show that TRPM4 is essential for pressure-induced SMC depolarization and myogenic constriction in the resistance vasculature.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.08.731006","type":"posted-content","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T18:30:23Z","timestamp":1781202623000},"source":"Crossref","is-referenced-by-count":3,"title":["TRPM4 Couples Mechanical Force to Myogenic Constriction Throughout the Resistance Vasculature"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0313-2119","authenticated-orcid":false,"given":"Wanchun","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medicine, Rochester, NY, USA 14624"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Sanchez\u2013Solano","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medicine, Rochester, NY, USA 14624"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6827-7095","authenticated-orcid":false,"given":"Boris","family":"Lavanderos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medicine, Rochester, NY, USA 14624"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyue","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medicine, Rochester, NY, USA 14624"},{"name":"Department of Medicine, University of Rochester Medicine, Rochester, NY, USA 14624"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumei","family":"Feng Earley","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medicine, Rochester, NY, USA 14624"},{"name":"Department of Medicine, University of Rochester Medicine, Rochester, NY, USA 14624"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9560-2941","authenticated-orcid":false,"given":"Scott","family":"Earley","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, University of Rochester Medicine, Rochester, NY, USA 14624"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026061311000594000_2026.06.08.731006v1.1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1902.sp000911"},{"key":"2026061311000594000_2026.06.08.731006v1.2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00053.2021"},{"key":"2026061311000594000_2026.06.08.731006v1.3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1998.199br.x"},{"key":"2026061311000594000_2026.06.08.731006v1.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.1998.211br.x"},{"key":"2026061311000594000_2026.06.08.731006v1.5","doi-asserted-by":"publisher","DOI":"10.1126\/science.270.5236.633"},{"key":"2026061311000594000_2026.06.08.731006v1.6","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1995.268.4.C799"},{"key":"2026061311000594000_2026.06.08.731006v1.7","doi-asserted-by":"publisher","DOI":"10.1161\/hh0302.105662"},{"key":"2026061311000594000_2026.06.08.731006v1.8","doi-asserted-by":"publisher","DOI":"10.1113\/JP281873"},{"key":"2026061311000594000_2026.06.08.731006v1.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2503186122"},{"key":"2026061311000594000_2026.06.08.731006v1.10","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2013.258319"},{"key":"2026061311000594000_2026.06.08.731006v1.11","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.42628"},{"key":"2026061311000594000_2026.06.08.731006v1.12","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000147311.54833.03"},{"key":"2026061311000594000_2026.06.08.731006v1.13","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004732"},{"key":"2026061311000594000_2026.06.08.731006v1.14","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.277145"},{"key":"2026061311000594000_2026.06.08.731006v1.15","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00550.2009"},{"key":"2026061311000594000_2026.06.08.731006v1.16","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00269.2010"},{"key":"2026061311000594000_2026.06.08.731006v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(02)00719-5"},{"key":"2026061311000594000_2026.06.08.731006v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/jcbfm.2014.139"},{"key":"2026061311000594000_2026.06.08.731006v1.19","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00582.2019"},{"key":"2026061311000594000_2026.06.08.731006v1.20","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.107.483404"},{"key":"2026061311000594000_2026.06.08.731006v1.21","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.238360"},{"key":"2026061311000594000_2026.06.08.731006v1.22","doi-asserted-by":"publisher","DOI":"10.1113\/JP274310"},{"key":"2026061311000594000_2026.06.08.731006v1.23","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.107.141069"},{"key":"2026061311000594000_2026.06.08.731006v1.24","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5c02015"},{"key":"2026061311000594000_2026.06.08.731006v1.25","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14220"},{"key":"2026061311000594000_2026.06.08.731006v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2011.11.004"},{"key":"2026061311000594000_2026.06.08.731006v1.27","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01021.2020"},{"key":"2026061311000594000_2026.06.08.731006v1.28","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.302882"},{"key":"2026061311000594000_2026.06.08.731006v1.29","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.16.6980-6989.2005"},{"key":"2026061311000594000_2026.06.08.731006v1.30","doi-asserted-by":"publisher","DOI":"10.1093\/ajh\/hpae134"},{"key":"2026061311000594000_2026.06.08.731006v1.31","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6451-10.2011"},{"key":"2026061311000594000_2026.06.08.731006v1.32","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2008.233"},{"key":"2026061311000594000_2026.06.08.731006v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1137"},{"key":"2026061311000594000_2026.06.08.731006v1.34","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00101.2010"},{"key":"2026061311000594000_2026.06.08.731006v1.35","doi-asserted-by":"publisher","DOI":"10.4161\/chan.5.3.15111"},{"key":"2026061311000594000_2026.06.08.731006v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/16711"},{"key":"2026061311000594000_2026.06.08.731006v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-025-00982-x"},{"key":"2026061311000594000_2026.06.08.731006v1.38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2217327120"},{"key":"2026061311000594000_2026.06.08.731006v1.39","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.adi3966"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.08.731006","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T18:00:14Z","timestamp":1781373614000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.08.731006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,11]]},"references-count":39,"URL":"https:\/\/doi.org\/10.64898\/2026.06.08.731006","relation":{},"subject":[],"published":{"date-parts":[[2026,6,11]]},"subtype":"preprint"}}