Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells
Hypoxia-induced pulmonary vascular constriction and structure remodeling are the main causes of hypoxic pulmonary hypertension. In the present study, an adeno-associated virus vector, containing Tie2 promoter and hypoxia response elements, was designed and named HTSFcAng(1-7). Its targeting, hypoxic...
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doaj-a5744dc7bec74bc1841a19c49870f0222020-11-25T03:08:36ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012020-06-0117975985Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial CellsMan-Ling Liu0Shu-Juan Xing1Xiao-Qing Liang2Ying Luo3Bo Zhang4Zhi-Chao Li5Ming-Qing Dong6Department of Physiology and Pathophysiology, Air Force Military Medical University (Fourth Military Medical University), Xi’an 710032, Shaanxi, PR ChinaXi’an International University, Xi’an 710077, Shaanxi, PR ChinaXi’an International University, Xi’an 710077, Shaanxi, PR ChinaDepartment of Physiology and Pathophysiology, Air Force Military Medical University (Fourth Military Medical University), Xi’an 710032, Shaanxi, PR ChinaDepartment of Physiology and Pathophysiology, Air Force Military Medical University (Fourth Military Medical University), Xi’an 710032, Shaanxi, PR ChinaSchool of Basic Medical Sciences, Northwest University, Xi’an 710069, Shaanxi, PR ChinaXi’an International University, Xi’an 710077, Shaanxi, PR China; Corresponding author: Ming-Qing Dong, PhD, Xi’an International University, Xi’an 710077, Shaanxi, PR China.Hypoxia-induced pulmonary vascular constriction and structure remodeling are the main causes of hypoxic pulmonary hypertension. In the present study, an adeno-associated virus vector, containing Tie2 promoter and hypoxia response elements, was designed and named HTSFcAng(1-7). Its targeting, hypoxic inducibility, and vascular relaxation were examined in vitro, and its therapeutic effects on hypobaric hypoxia-induced pulmonary hypertension were examined in rats. Transfection of HTSFcAng(1-7) specifically increased the expression of angiotensin-(1-7) in endothelial cells in normoxia. Hypoxia increased the expression of angiotensin-(1-7) in HTSFcAng(1-7)-transfected endothelial cells. The condition medium from HTSFcAng(1-7)-transfected endothelial cells inhibited the hypoxia-induced proliferation of pulmonary artery smooth muscle cells, relaxed the pulmonary artery rings, totally inhibited hypoxia-induced early contraction, enhanced maximum relaxation, and reversed phase II constriction to sustained relaxation. In hypoxic pulmonary hypertension rats, treatment with HTSFcAng(1-7) by nasal drip adeno-associated virus significantly reversed hypoxia-induced hemodynamic changes and pulmonary artery-wall remodeling, accompanied by the concomitant overexpression of angiotensin-(1-7), mainly in the endothelial cells in the lung. Therefore, hypoxia-inducible overexpression of angiotensin-(1-7) in pulmonary endothelial cells may be a potential strategy for the gene therapy of hypoxic pulmonary hypertension.http://www.sciencedirect.com/science/article/pii/S2329050120300681pulmonary hypertensionhypobaric hypoxiaadeno-associated virus vectorgene therapyangiotensin-(1-7) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Man-Ling Liu Shu-Juan Xing Xiao-Qing Liang Ying Luo Bo Zhang Zhi-Chao Li Ming-Qing Dong |
spellingShingle |
Man-Ling Liu Shu-Juan Xing Xiao-Qing Liang Ying Luo Bo Zhang Zhi-Chao Li Ming-Qing Dong Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells Molecular Therapy: Methods & Clinical Development pulmonary hypertension hypobaric hypoxia adeno-associated virus vector gene therapy angiotensin-(1-7) |
author_facet |
Man-Ling Liu Shu-Juan Xing Xiao-Qing Liang Ying Luo Bo Zhang Zhi-Chao Li Ming-Qing Dong |
author_sort |
Man-Ling Liu |
title |
Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells |
title_short |
Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells |
title_full |
Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells |
title_fullStr |
Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells |
title_full_unstemmed |
Reversal of Hypoxic Pulmonary Hypertension by Hypoxia-Inducible Overexpression of Angiotensin-(1-7) in Pulmonary Endothelial Cells |
title_sort |
reversal of hypoxic pulmonary hypertension by hypoxia-inducible overexpression of angiotensin-(1-7) in pulmonary endothelial cells |
publisher |
Elsevier |
series |
Molecular Therapy: Methods & Clinical Development |
issn |
2329-0501 |
publishDate |
2020-06-01 |
description |
Hypoxia-induced pulmonary vascular constriction and structure remodeling are the main causes of hypoxic pulmonary hypertension. In the present study, an adeno-associated virus vector, containing Tie2 promoter and hypoxia response elements, was designed and named HTSFcAng(1-7). Its targeting, hypoxic inducibility, and vascular relaxation were examined in vitro, and its therapeutic effects on hypobaric hypoxia-induced pulmonary hypertension were examined in rats. Transfection of HTSFcAng(1-7) specifically increased the expression of angiotensin-(1-7) in endothelial cells in normoxia. Hypoxia increased the expression of angiotensin-(1-7) in HTSFcAng(1-7)-transfected endothelial cells. The condition medium from HTSFcAng(1-7)-transfected endothelial cells inhibited the hypoxia-induced proliferation of pulmonary artery smooth muscle cells, relaxed the pulmonary artery rings, totally inhibited hypoxia-induced early contraction, enhanced maximum relaxation, and reversed phase II constriction to sustained relaxation. In hypoxic pulmonary hypertension rats, treatment with HTSFcAng(1-7) by nasal drip adeno-associated virus significantly reversed hypoxia-induced hemodynamic changes and pulmonary artery-wall remodeling, accompanied by the concomitant overexpression of angiotensin-(1-7), mainly in the endothelial cells in the lung. Therefore, hypoxia-inducible overexpression of angiotensin-(1-7) in pulmonary endothelial cells may be a potential strategy for the gene therapy of hypoxic pulmonary hypertension. |
topic |
pulmonary hypertension hypobaric hypoxia adeno-associated virus vector gene therapy angiotensin-(1-7) |
url |
http://www.sciencedirect.com/science/article/pii/S2329050120300681 |
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