CFTR and Vascular endothelial function

About This Grant

Abstract Misfolded/dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein causes multiple health related issues including lung disease and diabetes in cystic fibrosis (CF). Scientific advancements have significantly prolonged the life span of CF patients. But aging promotes endothelial dysfunction. Importantly, CF patients are known to have impaired endothelial function. Therefore, it is likely that endothelial dysfunction will worsen with age in CF patients. However, how CFTR regulates endothelial function and thereby vascular tone is not known. It is not known whether CFTR modulators are effective against CF-associated endothelial dysfunction. Therefore, it is important to understand the significance of CFTR in endothelial function and to assess the impact of aging on endothelial function in CF patients. Our preliminary data suggests that like CF patients, deletion of CFTR or expression of dysfunctional CFTR exhibit impairment of endothelium-dependent relaxation of coronary arteries in pigs. Even acute pharmacological inhibition of CFTR in mice aortic rings leads to endothelial dysfunction. We have also noted that genetic deletion of CFTR or pharmacological inhibition of CFTR downregulates endothelial nitric oxide synthase (eNOS) expression in endothelial cells. As aging promotes endothelial dysfunction and downregulation of eNOS levels, we propose to evaluate the changes in endothelial function and examine the mechanism involved in CFTR-mediated regulation of NO production with aging. We will use a novel mouse model of CF disease with endothelial deletion of CFTR (e-CFTR-/-) to determine: 1) whether aging-induced endothelial dysfunction accelerates with endothelial deletion of CFTR and 2) the eNOS- CFTR regulation as a mechanism mediating the CFTR-dependent regulation of endothelial function. We will examine vascular function in aged mice having endothelial deletion of CFTR. We will also use cell biology-based assays to determine the functional changes in the endothelial cells due to CFTR and possible ways to modulate such effect. This study will demonstrate the impact of aging on endothelial dysfunction due to loss of CFTR function.