Original articles
Huaqing Zheng, Xiaolong Li, Xin Zeng, Chengcui Huang, Mingming Ma, Xiaofei Lv, Yajuan Zhang, Lu Sun, Guanlei Wang, Yanhua Du, Yongyuan Guan. TMEM16A inhibits angiotensin II-induced basilar artery smooth muscle cell migration in a WNK1-dependent manner[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3994-4007

TMEM16A inhibits angiotensin II-induced basilar artery smooth muscle cell migration in a WNK1-dependent manner
Huaqing Zheng, Xiaolong Li, Xin Zeng, Chengcui Huang, Mingming Ma, Xiaofei Lv, Yajuan Zhang, Lu Sun, Guanlei Wang, Yanhua Du, Yongyuan Guan
Department of Pharmacology, Cardiac & Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China
Vascular smooth muscle cell (VSMC) migration plays a critical role in the pathogenesis of many cardiovascular diseases. We recently showed that TMEM16A is involved in hypertension-induced cerebrovascular remodeling. However, it is unclear whether this effect is related to the regulation of VSMC migration. Here, we investigated whether and how TMEM16A contributes to migration in basilar artery smooth muscle cells (BASMCs). We observed that AngII increased the migration of cultured BASMCs, which was markedly inhibited by overexpression of TMEM16A. TMEM16A overexpression inhibited AngII-induced RhoA/ROCK2 activation, and myosin light chain phosphatase (MLCP) and myosin light chain (MLC20) phosphorylation. But AngII-induced myosin light chain kinase (MLCK) activation was not affected by TMEM16A. Furthermore, a suppressed activation of integrinβ3/FAK pathway, determined by reduced integrinβ3 expression, FAK phosphorylation and F-actin rearrangement, was observed in TMEM16A-overexpressing BASMCs upon AngII stimulation. Contrary to the results of TMEM16A overexpression, silencing of TMEM16A showed the opposite effects. These in vitro results were further demonstrated in vivo in basilar arteries from VSMC-specific TMEM16A transgenic mice during AngII-induced hypertension. Moreover, we observed that the inhibitory effect of TMEM16A on BASMC migration was mediated by decreasing the activation of WNK1, a Cl--sensitive serine/threonine kinase. In conclusion, this study demonstrated that TMEM16A suppressed AngII-induced BASMC migration, thus contributing to the protection against cerebrovascular remodeling during AngII-infused hypertension. TMEM16A may exert this effect by suppressing the RhoA/ROCK2/MLCP/MLC20 and integrinβ3/FAK signaling pathways via inhibiting WNK1. Our results suggest that TMEM16A may serve as a novel therapeutic target for VSMC migration-related diseases, such as vascular remodeling.
Key words:    TMEM16A    Integrin    RhoA/ROCK    VSMC migration    Vascular remodeling    WNK1    Hypertension    FAK   
Received: 2021-01-25     Revised: 2021-03-18
DOI: 10.1016/j.apsb.2021.04.013
Funds: This work was supported by the National Natural Science Foundation of China (grant Nos. 81872858, 81773721, 81573422, and 81903598).
Corresponding author: Yanhua Du,E-mail:duyanhua@mail.sysu.edu.cn;Yongyuan Guan,E-mail:guanyy@mail.sysu.edu.cn     Email:duyanhua@mail.sysu.edu.cn;guanyy@mail.sysu.edu.cn
Author description:
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Huaqing Zheng
Xiaolong Li
Xin Zeng
Chengcui Huang
Mingming Ma
Xiaofei Lv
Yajuan Zhang
Lu Sun
Guanlei Wang
Yanhua Du
Yongyuan Guan

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