CFTR deficiency aggravates Ang II induced vasoconstriction and hypertension by regulating Ca2+ influx and RhoA/Rock pathway in VSMCs

Cystic fibrosis transmembrane conductance regulator (CFTR) has been associated with vascular tone and blood pressure (BP), however, its role in the genesis of hypertension remains elusive. In the present study, we investigated the regulating effect of CFTR on angiotensin II (Ang II) -induced hyperte...

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Published in:Frontiers in bioscience (Landmark. Print) 2021-12, Vol.26 (12), p.1396-1410
Main Authors: Zhao, Liyan, Yuan, Feng, Pan, Ni, Yu, Yun, Yang, Hanyan, Liu, Yaosheng, Wang, Ruomei, Zhang, Bin, Wang, Guanlei
Format: Article
Language:English
Subjects:
Angiotensin II - metabolism
Angiotensin II - pharmacology
Animals
Calcium - metabolism
Cells, Cultured
Cystic Fibrosis Transmembrane Conductance Regulator - genetics
Cystic Fibrosis Transmembrane Conductance Regulator - metabolism
Hypertension - genetics
Hypertension - metabolism
Mice
Mice, Inbred CFTR
Mice, Knockout
Muscle, Smooth, Vascular - cytology
Phosphorylation
rho-Associated Kinases
rhoA GTP-Binding Protein - metabolism
Vasoconstriction
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Summary:Cystic fibrosis transmembrane conductance regulator (CFTR) has been associated with vascular tone and blood pressure (BP), however, its role in the genesis of hypertension remains elusive. In the present study, we investigated the regulating effect of CFTR on angiotensin II (Ang II) -induced hypertension and defined the molecular role of CFTR in vasoconstriction. We found that CFTR mRNA and protein expression were markedly down-regulated in the arteries from Ang II induced hypertensive animals. During the development of hypertension, BP of Cftr-⁣/- mice was significantly higher than that of Cftr+⁣/+ mice. Arteries from Cftr-⁣/- mice or pre-incubated with CFTR specific inhibitor CFTR(inh)-172 exhibited a greater contractile response to Ang II. In vascular smooth muscle cells (VSMCs), the phosphorylation of myosin light chain (MLC), which is the core of VSMCs contraction, was negatively modulated by CFTR. Furthermore, intracellular Ca2+ concentration ([Ca2+]i) rise in response to Ang II was negatively modulated by CFTR, while no alteration was observed in resting VSMCs. Ras homolog family member A/Rho-associated protein kinase (RhoA/Rock) mediated phosphorylation of myosin phosphatase target subunit 1 (MYPT1), a regulator of MLC phosphorylation, was negatively modulated by CFTR in both resting and Ang II-stimulated VSMCs. This study demonstrates that CFTR is a negative regulator of vasoconstriction and hypertension, and the underlying mechanism contains two possible pathways: (1) in resting VSMCs, CFTR altered MLC phosphorylation through RhoA/Rock pathway; (2) in Ang II stimulated VSMCs, the regulating effect was mediated by both Ca2+ influx and RhoA/Rock mediated pathway.
ISSN:2768-6698
DOI:10.52586/5034