{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T03:36:28Z","timestamp":1792640188837,"version":"4.5.0"},"reference-count":75,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2017,12,2]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Recent studies demonstrate that spatially restricted, local Ca\n              <jats:sup>2+<\/jats:sup>\n              signals are key regulators of endothelium\u2010dependent vasodilation in systemic circulation. There are drastic functional differences between pulmonary arteries (\n              <jats:styled-content style=\"fixed-case\">PA<\/jats:styled-content>\n              s) and systemic arteries, but the local Ca\n              <jats:sup>2+<\/jats:sup>\n              signals that control endothelium\u2010dependent vasodilation of\n              <jats:styled-content style=\"fixed-case\">PA<\/jats:styled-content>\n              s are not known. Localized, unitary Ca\n              <jats:sup>2+<\/jats:sup>\n              influx events through transient receptor potential vanilloid 4 (\n              <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>\n              4) channels, termed\n              <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>\n              4 sparklets, regulate endothelium\u2010dependent vasodilation in resistance\u2010sized mesenteric arteries via activation of Ca\n              <jats:sup>2+<\/jats:sup>\n              \u2010dependent K\n              <jats:sup>+<\/jats:sup>\n              channels. The objective of this study was to determine the unique functional roles, signaling targets, and endogenous regulators of\n              <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>\n              4 sparklets in resistance\u2010sized\n              <jats:styled-content style=\"fixed-case\">PA<\/jats:styled-content>\n              s.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Using confocal imaging, custom image analysis, and pressure myography in fourth\u2010order\n              <jats:styled-content style=\"fixed-case\">PA<\/jats:styled-content>\n              s in conjunction with knockout mouse models, we report a novel Ca\n              <jats:sup>2+<\/jats:sup>\n              signaling mechanism that regulates endothelium\u2010dependent vasodilation in resistance\u2010sized\n              <jats:styled-content style=\"fixed-case\">PA<\/jats:styled-content>\n              s.\n              <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>\n              4 sparklets exhibit distinct spatial localization in\n              <jats:styled-content style=\"fixed-case\">PA<\/jats:styled-content>\n              s when compared with mesenteric arteries, and preferentially activate endothelial nitric oxide synthase (\n              <jats:styled-content style=\"fixed-case\">eNOS<\/jats:styled-content>\n              ). Nitric oxide released by\n              <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>\n              4\u2010endothelial nitric oxide synthase signaling not only promotes vasodilation, but also initiates a guanylyl cyclase\u2010protein kinase G\u2010dependent negative feedback loop that inhibits cooperative openings of\n              <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>\n              4 channels, thus limiting sparklet activity. Moreover, we discovered that adenosine triphosphate dilates\n              <jats:styled-content style=\"fixed-case\">PA<\/jats:styled-content>\n              s through a P2 purinergic receptor\u2010dependent activation of\n              <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>\n              4 sparklets.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Our results reveal a spatially distinct\n              <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>\n              4\u2010endothelial nitric oxide synthase signaling mechanism and its novel endogenous regulators in resistance\u2010sized\n              <jats:styled-content style=\"fixed-case\">PA<\/jats:styled-content>\n              s.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.117.007157","type":"journal-article","created":{"date-parts":[[2017,12,24]],"date-time":"2017-12-24T01:10:33Z","timestamp":1514077833000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":81,"title":["Nitric Oxide\u2013Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries"],"prefix":"10.1161","volume":"6","author":[{"given":"Corina","family":"Marziano","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA"},{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwangseok","family":"Hong","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric L.","family":"Cope","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael I.","family":"Kotlikoff","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brant E.","family":"Isakson","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA"},{"name":"Robert M. 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