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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,4,9]]},"abstract":"<jats:p>\n                    Endothelial cells (ECs) line the wall of blood vessels and regulate arterial contractility to tune regional organ blood flow and systemic pressure. Chloride (Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    ) is the most abundant anion in ECs and the Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    sensitive With-No-Lysine (WNK) kinase is expressed in this cell type. Whether intracellular Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    signaling and WNK kinase regulate EC function to alter arterial contractility is unclear. Here, we tested the hypothesis that intracellular Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    signaling in ECs regulates arterial contractility and examined the signaling mechanisms involved, including the participation of WNK kinase. Our data obtained using two-photon microscopy and cell-specific inducible knockout mice indicated that acetylcholine, a prototypical vasodilator, stimulated a rapid reduction in intracellular Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    concentration ([Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    ) due to the activation of TMEM16A, a Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    channel, in ECs of resistance-size arteries. TMEM16A channel-mediated Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    signaling activated WNK kinase, which phosphorylated its substrate proteins SPAK and OSR1 in ECs. OSR1 potentiated transient receptor potential vanilloid 4 (TRPV4) currents in a kinase-dependent manner and required a conserved binding motif located in the channel C terminus. Intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling was measured in four dimensions in ECs using a high-speed lightsheet microscope. WNK kinase-dependent activation of TRPV4 channels increased local intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    signaling in ECs and produced vasodilation. In summary, we show that TMEM16A channel activation reduces [Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    , which activates WNK kinase in ECs. WNK kinase phosphorylates OSR1 which then stimulates TRPV4 channels to produce vasodilation. Thus, TMEM16A channels regulate intracellular Cl\n                    <jats:sup>\u2212<\/jats:sup>\n                    signaling and WNK kinase activity in ECs to control arterial contractility.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2322135121","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T13:41:11Z","timestamp":1712151671000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":23,"title":["WNK kinase is a vasoactive chloride sensor in endothelial cells"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7900-7939","authenticated-orcid":false,"given":"Tessa A. C.","family":"Garrud","sequence":"first","affiliation":[{"name":"Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9797-6402","authenticated-orcid":false,"given":"Briar","family":"Bell","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163"},{"name":"Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1831-7842","authenticated-orcid":false,"given":"Alejandro","family":"Mata-Daboin","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1190-5433","authenticated-orcid":false,"given":"Dieniffer","family":"Peixoto-Neves","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9431-9271","authenticated-orcid":false,"given":"Daniel M.","family":"Collier","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio F.","family":"Cordero-Morales","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163"},{"name":"Department of Biochemistry and Molecular Biology, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1505-3335","authenticated-orcid":false,"given":"Jonathan H.","family":"Jaggar","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 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