{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:32:22Z","timestamp":1790645542195,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T00:00:00Z","timestamp":1598572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["DK-MOLIN - W1241"],"award-info":[{"award-number":["DK-MOLIN - W1241"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Endothelial dysfunction is one of the hallmarks of different vascular diseases, including pulmonary arterial hypertension (PAH). Ion channelome changes have long been connected to vascular remodeling in PAH, yet only recently has the focus shifted towards Ca2+-activated Cl\u2212 channels (CaCC). The most prominent member of the CaCC TMEM16A has been shown to contribute to the pathogenesis of idiopathic PAH (IPAH) in pulmonary arterial smooth muscle cells, however its role in the homeostasis of healthy human pulmonary arterial endothelial cells (PAECs) and in the development of endothelial dysfunction remains underrepresented. Here we report enhanced TMEM16A activity in IPAH PAECs by whole-cell patch-clamp recordings. Using adenoviral-mediated TMEM16A increase in healthy primary human PAECs in vitro and in human pulmonary arteries ex vivo, we demonstrate the functional consequences of the augmented TMEM16A activity: alterations of Ca2+ dynamics and eNOS activity as well as decreased NO production, PAECs proliferation, wound healing, tube formation and acetylcholine-mediated relaxation of human pulmonary arteries. We propose that the ERK1\/2 pathway is specifically affected by elevated TMEM16A activity, leading to these pathological changes. With this work we introduce increased TMEM16A activity in the cell membrane of human PAECs for the development of endothelial dysfunction in PAH.<\/jats:p>","DOI":"10.3390\/cells9091984","type":"journal-article","created":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T10:23:08Z","timestamp":1598610188000},"page":"1984","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries"],"prefix":"10.3390","volume":"9","author":[{"given":"Davor","family":"Skofic Maurer","sequence":"first","affiliation":[{"name":"Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstra\u00dfe 6, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Zabini","sequence":"additional","affiliation":[{"name":"Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstra\u00dfe 6, 8010 Graz, Austria"},{"name":"Ludwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstra\u00dfe 6, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandran","family":"Nagaraj","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstra\u00dfe 6, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neha","family":"Sharma","sequence":"additional","affiliation":[{"name":"Experimental Anaesthesiology, Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 5, 8036 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6382-6369","authenticated-orcid":false,"given":"Mikl\u00f3s","family":"Lengyel","sequence":"additional","affiliation":[{"name":"Department of Physiology, Semmelweis University, T\u0171zolt\u00f3 utca 37-47, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3955-4863","authenticated-orcid":false,"given":"Bence M.","family":"Nagy","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstra\u00dfe 6, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sa\u0161a","family":"Frank","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstra\u00dfe 6, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Klepetko","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Medical University of Vienna, W\u00e4hringer G\u00fcrtel 18-20, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0618-7342","authenticated-orcid":false,"given":"Elisabeth","family":"Gschwandtner","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Medical University of Vienna, W\u00e4hringer G\u00fcrtel 18-20, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e9ter","family":"Enyedi","sequence":"additional","affiliation":[{"name":"Department of Physiology, Semmelweis University, T\u0171zolt\u00f3 utca 37-47, 1094 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grazyna","family":"Kwapiszewska","sequence":"additional","affiliation":[{"name":"Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstra\u00dfe 6, 8010 Graz, Austria"},{"name":"Ludwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstra\u00dfe 6, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horst","family":"Olschewski","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstra\u00dfe 6, 8010 Graz, Austria"},{"name":"Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, Neue Stiftingtalstra\u00dfe 6, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Olschewski","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstra\u00dfe 6, 8010 Graz, Austria"},{"name":"Experimental Anaesthesiology, Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 5, 8036 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"552","DOI":"10.3389\/fphys.2020.00552","article-title":"Blood Flow Forces in Shaping the Vascular System: A Focus on Endothelial Cell Behavior","volume":"11","author":"Campinho","year":"2020","journal-title":"Front. 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