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

Abstract

Background: 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. Results: 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 Ca 2+ concentration ([Ca 2+ ] 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. Conclusions: 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 Ca 2+ influx and RhoA/Rock mediated pathway.

Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters

“…This finding is in agreement with previous studies reporting cross talks between the CFTR function or processing and the RhoA/ROCK pathway, including Refs. [ 40 , 41 , 42 ]. APEX2 and TurboID proximity labeling also enabled the identification of interaction partners of CFTR folding, including chaperones and proteins involved in the ubiquitination process ( Supplementary Figure S1B,C ).…”

CFTR Suppresses Neointimal Formation Through Attenuating Proliferation and Migration of Aortic Smooth Muscle Cells

“…We have previously shown that the CFTR gene is widely expressed in VSMCs. 11 , 17 To determine the role of CFTR in pathological vascular remodeling, we examined its protein expression in balloon-injured rat carotid arteries. The CFTR protein levels in the VSMC media of carotid arteries decreased progressively (Fig.…”

Fat‐Diets in Perinatal Stages Altered Nr3c2‐Mediated Ca2+ Currents in Mesenteric Arteries of Offspring Rats

“…[20] Multiple hormones have been shown their effects via Ca 2+ influx. [4,5] There has been very limited data on the influence of mineralocorticoid hormones on Ca 2+ currents in vascular SMCs. This study also was the first to demonstrate that malnutrition in pregnancy could impact on a mineralocorticoid hormone-mediated Ca 2+ flow via LTCC in the SMCs from the offspring resistance arteries.…”

“…[ 2,3 ] Number of hormones have been demonstrated to exert their effects via increase of Ca 2+ currents. [ 4–6 ] Previous studies showed that an increase of aldosterone in the circulation could cause changes of Ca 2+ influx in the cardiac tissue, [ 7 ] and an aldosterone receptor knock‐out model demonstrated an altered vasoconstriction, [ 8 ] indicating involvement of aldosterone and its receptors in regulations of vascular tension and blood pressure. The present study tested aldosterone and its receptors and their effects on Ca 2+ currents/transients in vascular SMCs.…”