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Article

Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries

by
Davor Skofic Maurer
1,
Diana Zabini
1,2,
Chandran Nagaraj
2,
Neha Sharma
3,
Miklós Lengyel
4,
Bence M. Nagy
2,
Saša Frank
5,
Walter Klepetko
6,
Elisabeth Gschwandtner
6,
Péter Enyedi
4,
Grazyna Kwapiszewska
1,2,
Horst Olschewski
2,7 and
Andrea Olschewski
2,3,*
1
Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
2
Ludwig Boltzmann Institute for Lung Vascular Research, Neue Stiftingtalstraße 6, 8010 Graz, Austria
3
Experimental Anaesthesiology, Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 5, 8036 Graz, Austria
4
Department of Physiology, Semmelweis University, Tűzoltó utca 37-47, 1094 Budapest, Hungary
5
Gottfried Schatz Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
6
Department of Thoracic Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria
7
Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
*
Author to whom correspondence should be addressed.
Cells 2020, 9(9), 1984; https://doi.org/10.3390/cells9091984
Received: 21 July 2020 / Revised: 21 August 2020 / Accepted: 26 August 2020 / Published: 28 August 2020
(This article belongs to the Special Issue Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms)
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Abstract

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− 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. View Full-Text
Keywords: TMEM16A; Ano1; pulmonary endothelial cells; endothelial dysfunction; pulmonary hypertension; intracellular calcium; angiogenesis; eNOS uncoupling; benzbromarone; metabolic switch TMEM16A; Ano1; pulmonary endothelial cells; endothelial dysfunction; pulmonary hypertension; intracellular calcium; angiogenesis; eNOS uncoupling; benzbromarone; metabolic switch
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MDPI and ACS Style

Skofic Maurer, D.; Zabini, D.; Nagaraj, C.; Sharma, N.; Lengyel, M.; Nagy, B.M.; Frank, S.; Klepetko, W.; Gschwandtner, E.; Enyedi, P.; Kwapiszewska, G.; Olschewski, H.; Olschewski, A. Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries. Cells 2020, 9, 1984. https://doi.org/10.3390/cells9091984

AMA Style

Skofic Maurer D, Zabini D, Nagaraj C, Sharma N, Lengyel M, Nagy BM, Frank S, Klepetko W, Gschwandtner E, Enyedi P, Kwapiszewska G, Olschewski H, Olschewski A. Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries. Cells. 2020; 9(9):1984. https://doi.org/10.3390/cells9091984

Chicago/Turabian Style

Skofic Maurer, Davor, Diana Zabini, Chandran Nagaraj, Neha Sharma, Miklós Lengyel, Bence M. Nagy, Saša Frank, Walter Klepetko, Elisabeth Gschwandtner, Péter Enyedi, Grazyna Kwapiszewska, Horst Olschewski, and Andrea Olschewski. 2020. "Endothelial Dysfunction Following Enhanced TMEM16A Activity in Human Pulmonary Arteries" Cells 9, no. 9: 1984. https://doi.org/10.3390/cells9091984

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