TMEM16A inhibits angiotensin Ⅱ-induced basilar artery smooth muscle cell migration in a WNK1-dependent manner

• 作者: Huaqing Zheng Xiaolong Li Xin Zeng Chengcui Huang Mingming Ma Xiaofei Lv Yajuan Zhang Lu Sun Guanlei Wang Yanhua Du Yongyuan Guan
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（12）
• 所属期刊栏目: Original articles
• 页码范围: 3994-4007
• 页数: 14页
• 语种: 英文

摘要

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 overex-pression 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/thre-onine 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 in-tegrinβ3/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.