Introduction: Cystic fibrosis transmembrane conductance regulator (CFTR) functions as a cAMP-dependent chloride channel, has primarily been studied in the secretary epithelia, where the mutation in the CFTR leads to classic CF phenotype. CFTR has been linked to vascular tone regulation and clinical hypotension. The study aims to examine whether CFTR plays a role in cerebrovascular pathological changes during hypertension.
Methods: The wild type (WT) and CFTR null mice were implanted with mini-osmotic pumps loaded with Ang II (1000ng/kg/min) to establish Ang-II induced hypertension model. The 2-kidney-2-clip (2k2c), stroke prone hypertensive rats was also applied.
Results: There is no significant difference in systolic blood pressure (SBP) and basilar arterial morphological features between WT and CFTR-/- mice. However, after Ang-II infusion, SBP and medial cross-sectional area, media thickness, and media-lumen ratio of the basilar artery was significantly increased in CFTR-/- mice, indicating that CFTR deficiency exacerbates hypertension and cerebrovascular remodeling. The exacerbating cerebrovascular remodeling was confirmed by the disarray of VSMCs and extracellular matrix accumulation using electron microcopy; by enhanced VSMC proliferation using BrdU assay and VSMC differentiation marker gene analysis. Moreover, CFTR protein/mRNA expression in hypertensive basilar arteries was markedly reduced and negatively correlated with the level of SBP. In vitro, Ang-II (100nM) induced BASMCs proliferation and the phenotype switch from a contractile to a proliferative type, accompanied by a decrease in CFTR protein expression. Adenovirus-mediated hCFTR overexpression inhibited, whereas CFTR siRNA enhanced Ang II-induced proliferation and cell cycle transition from G0/G1 to S phase via modulating cyclin D1, cyclin E and p21. Moreover, CFTR was required for AT1R-RhoA-p38 MAPK pathway activated by Ang II, which reduced CFTR channel activation and thus activated AT1R-mediated signaling.
Conclusion: Our findings indicated that CFTR deficiency promotes the development of hypertension, which may be ascribed to CFTR negatively modulating hypertension-related VSMC proliferative phenotype switch and cerebrovascular remodeling.