Renin-angiotensin system regulates pulmonary arterial smooth muscle cell migration in chronic thromboembolic pulmonary hypertension

Pulmonary arterial smooth muscle cell (PASMC) migration plays a key role in vascular remodeling, which occurs during development of chronic thromboembolic pulmonary hypertension (CTEPH). Activation of the renin-angiotensin system (RAS) contributes to vascular remodeling observed in many diseases, in...

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Published in:American journal of physiology. Lung cellular and molecular physiology 2018-02, Vol.314 (2), p.L276-L286
Main Authors: Zhang, Yun-Xia, Li, Ji-Feng, Yang, Yuan-Hua, Zhai, Zhen-Guo, Gu, Song, Liu, Yan, Miao, Ran, Zhong, Ping-Ping, Wang, Ying, Huang, Xiao-Xi, Wang, Chen
Format: Article
Language:English
Subjects:
Angiotensin II - metabolism
Cell Movement
Cell Proliferation
Cells, Cultured
Female
Humans
Hypertension, Pulmonary - metabolism
Hypertension, Pulmonary - pathology
Male
MAP Kinase Signaling System
Middle Aged
Mitogen-Activated Protein Kinases
Muscle, Smooth, Vascular - metabolism
Muscle, Smooth, Vascular - pathology
Phosphorylation
Pulmonary Artery - metabolism
Pulmonary Artery - pathology
Renin - metabolism
Renin-Angiotensin System
Signal Transduction
Thromboembolism - metabolism
Thromboembolism - pathology
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Summary:Pulmonary arterial smooth muscle cell (PASMC) migration plays a key role in vascular remodeling, which occurs during development of chronic thromboembolic pulmonary hypertension (CTEPH). Activation of the renin-angiotensin system (RAS) contributes to vascular remodeling observed in many diseases, including idiopathic pulmonary arterial hypertension. However, the role of RAS imbalance in CTEPH has not been characterized. Here, we hypothesize that RAS imbalance regulates vascular remodeling by promoting PASMC migration in CTEPH. Serum renin and angiotensin II levels in patients with CTEPH were quantified by ELISA. The pulmonary endarterectomy tissues were stained and analyzed by immunohistochemistry. PASMCs were isolated and verified by immunofluorescence staining. PASMC migration was determined by Transwell assay. Phosphorylation and protein level were detected by Western blotting. Serum levels of renin and angiotensin II were increased in patients with CTEPH {renin [median (25th percentile, 75th percentile) in pg/ml], 1,199.94 [690.85, 1,656.90] vs. 595.43 [351.48, 936.43], P < 0.001; angiotensin II [in pg/ml], 63.97 [45.97, 345.24] vs. 56.85 [11.20, 90.37], P < 0.05}. The migration of PASMCs isolated from patients with CTEPH was enhanced compared with control. Angiotensin II promoted the migration of PASMCs via activation of angiotensin II receptor 1 and phosphorylation of ERK1/2, whereas angiotensin-(1-7) counteracted this effect through activation of the Mas receptor and ERK1/2. These results demonstrate that the renin-angiotensin system regulates migration of PASMCs from patients with CTEPH via the ERK1/2 pathway. Our findings suggest that angiotensin-(1-7) or reagents targeting the renin-angiotensin system will be beneficial in the development of novel therapies for CTEPH.
ISSN:1040-0605
1522-1504
DOI:10.1152/ajplung.00515.2016