Disruption of CFTR chloride channel alters mechanical properties and cAMP‐dependent Cl⁻ transport of mouse aortic smooth muscle cells

Abstract

Chloride (Cl -) channels expressed in vascular smooth muscle cells (VSMC) are important to control membrane potential equilibrium, intracellular pH, cell volume maintenance, contraction, relaxation and proliferation. The present study was designed to compare the expression, regulation and function of CFTR Cl -channels in aortic VSMC from Cftr +/+ and Cftr -/-mice. Using an iodide efflux assay we demonstrated stimulation of CFTR by VIP, isoproterenol, cAMP agonists and other pharmacological activators in cultured VSMC from Cftr +/+ . On the contrary, in cultured VSMC from Cftr -/-mice these agonists have no effect, showing that CFTR is the dominant Cl -channel involved in the response to cAMP mediators. Angiotensin II and the calcium ionophore A23187 stimulated Ca 2+ -dependent Cl -channels in VSMCs from both genotypes. CFTR was activated in myocytes maintained in medium containing either high potassium or 5-hydroxytryptamine (5-HT) and was inhibited by CFTR inh -172, glibenclamide and diphenylamine-2,2 -dicarboxylic acid (DPC). We also examined the mechanical properties of aortas. Arteries with or without endothelium from Cftr -/-mice became significantly more constricted (∼2-fold) than that of Cftr +/+ mice in response to vasoactive agents. Moreover, in precontracted arteries of Cftr +/+ mice, VIP and CFTR activators induced vasorelaxation that was altered in Cftr -/-mice. Our findings suggest a novel mechanism for regulation of the vascular tone by cAMP-dependent CFTR chloride channels in VSMC. To our knowledge this study is the first to report the phenotypic consequences of the loss of a Cl -channel on vascular reactivity.

Pulmonary vascular dysfunction in end-stage cystic fibrosis: role of NF-κB and endothelin-1

“…Alternative hypothesis could be that genistein is a strong CFTR potentiator [36]. The latter has recently been demonstrated to be markedly involved in vasodilation [37][38][39]. In addition, genistein could act through its wide enhancing effects on the transcription of vasodilative proteins, some of them involving different tyrosine kinase activities.…”

Expression and function of cystic fibrosis transmembrane conductance regulator in rat intrapulmonary arteries

“…The CFTR was generally regarded as specifically expressed in epithelial cells until evidence for CFTR expression in nonepithelial tissues emerged. CFTR is expressed in cardiac muscle cells [2], brain [3] and endothelia [4], and has recently been found in tracheal smooth muscle cells (SMCs) [5] and aortic SMCs of rats and mice [6,7]. Despite this CFTR expression profile, the clinical picture of patients suffering from the CFTR-related disease cystic fibrosis appears to be unrelated to cardiac, vascular and brain dysfunction.…”

Cystic Fibrosis Transmembrane Conductance Regulator Protein (CFTR) Expression in the Developing Human Brain

“…Lung involvement is the major cause of mortality in these patients and is dominated by recurrent infections and obstruction, finally leading to respiratory failure. Over the past 20 years, CFTR protein and its mRNA expression have progressively been reported to be present in epithelial cells of many other organs, such as the kidney (Todd-Turla et al 1996;Devuyst et al 1996), smooth muscle cells, immune cells, cardiac myocytes (Robert et al 2005) and neurons of the adult central nervous system (CNS) (Mulberg et al 1995;Johannesson et al 1997;Niu et al 2009;Guo et al 2009a;2009b). In addition, several studies have reported the expression of CFTR very early during development in immature cells of the same organs as in adulthood, suggesting a previously unsuspected role for CFTR during development (Harris et al 1991;Tizzano et al 1993).…”