CFTR Therapeutics Normalize Cerebral Perfusion Deficits in Mouse Models of Heart Failure and Subarachnoid Hemorrhage

Abstract

Heart failure (HF) and subarachnoid hemorrhage (SAH) chronically reduce cerebral perfusion, which negatively affects clinical outcome. This work demonstrates a strong relationship between cerebral artery cystic fibrosis transmembrane conductance regulator (CFTR) expression and altered cerebrovascular reactivity in HF and SAH. In HF and SAH, CFTR corrector compounds (C18 or lumacaftor) normalize pathological alterations in cerebral artery CFTR expression, vascular reactivity, and cerebral perfusion, without affecting systemic hemodynamic parameters. This normalization correlates with reduced neuronal injury. Therefore, CFTR therapeutics have emerged as valuable clinical tools to manage cerebrovascular dysfunction, impaired cerebral perfusion, and neuronal injury.

Keywords: CBF, cerebral blood flow; CFTR, cystic fibrosis transmembrane conductance regulator; HF, heart failure; MAP, mean arterial pressure; MOPS, 3-morpholinopropanesulfonic acid; MRI, magnetic resonance imaging; NIH, National Institutes of Health; PCA, posterior cerebral artery; S1P, sphingosine-1-phosphate; SAH, subarachnoid hemorrhage; TNF, tumor necrosis factor; TPR, total peripheral resistance; cognitive impairment; corrector compounds; cystic fibrosis transmembrane conductance regulator (CFTR); myogenic vasoconstriction; sphingosine-1-phosphate; tumor necrosis factor; vascular smooth muscle cells.