Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries
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 Ca<sup>2+</sup>-activated Cl<...
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MDPI AG
2020-08-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/9/1984 |
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| author | Davor Skofic Maurer Diana Zabini Chandran Nagaraj Neha Sharma Miklós Lengyel Bence M. Nagy Saša Frank Walter Klepetko Elisabeth Gschwandtner Péter Enyedi Grazyna Kwapiszewska Horst Olschewski Andrea Olschewski |
| author_facet | Davor Skofic Maurer Diana Zabini Chandran Nagaraj Neha Sharma Miklós Lengyel Bence M. Nagy Saša Frank Walter Klepetko Elisabeth Gschwandtner Péter Enyedi Grazyna Kwapiszewska Horst Olschewski Andrea Olschewski |
| author_sort | Davor Skofic Maurer |
| collection | DOAJ |
| description | 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 Ca<sup>2+</sup>-activated Cl<sup>−</sup> 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 Ca<sup>2+</sup> 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. |
| first_indexed | 2024-03-10T16:44:09Z |
| format | Article |
| id | doaj.art-b536953ba5f2429ba5b9350f3ff020f6 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T16:44:09Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-b536953ba5f2429ba5b9350f3ff020f62023-11-20T11:46:58ZengMDPI AGCells2073-44092020-08-0199198410.3390/cells9091984Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary ArteriesDavor Skofic Maurer0Diana Zabini1Chandran Nagaraj2Neha Sharma3Miklós Lengyel4Bence M. Nagy5Saša Frank6Walter Klepetko7Elisabeth Gschwandtner8Péter Enyedi9Grazyna Kwapiszewska10Horst Olschewski11Andrea Olschewski12Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, AustriaOtto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, AustriaLudwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstraße 6, 8010 Graz, AustriaExperimental Anaesthesiology, Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 5, 8036 Graz, AustriaDepartment of Physiology, Semmelweis University, Tűzoltó utca 37-47, 1094 Budapest, HungaryLudwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstraße 6, 8010 Graz, AustriaGottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, AustriaDepartment of Thoracic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, AustriaDepartment of Thoracic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, AustriaDepartment of Physiology, Semmelweis University, Tűzoltó utca 37-47, 1094 Budapest, HungaryOtto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, AustriaLudwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstraße 6, 8010 Graz, AustriaLudwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstraße 6, 8010 Graz, AustriaEndothelial 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 Ca<sup>2+</sup>-activated Cl<sup>−</sup> 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 Ca<sup>2+</sup> 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.https://www.mdpi.com/2073-4409/9/9/1984TMEM16AAno1pulmonary endothelial cellsendothelial dysfunctionpulmonary hypertensionintracellular calcium |
| spellingShingle | Davor Skofic Maurer Diana Zabini Chandran Nagaraj Neha Sharma Miklós Lengyel Bence M. Nagy Saša Frank Walter Klepetko Elisabeth Gschwandtner Péter Enyedi Grazyna Kwapiszewska Horst Olschewski Andrea Olschewski Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries Cells TMEM16A Ano1 pulmonary endothelial cells endothelial dysfunction pulmonary hypertension intracellular calcium |
| title | Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries |
| title_full | Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries |
| title_fullStr | Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries |
| title_full_unstemmed | Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries |
| title_short | Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries |
| title_sort | endothelial dysfunction following enhanced tmem16a activity in human pulmonary arteries |
| topic | TMEM16A Ano1 pulmonary endothelial cells endothelial dysfunction pulmonary hypertension intracellular calcium |
| url | https://www.mdpi.com/2073-4409/9/9/1984 |
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