Heart Failure Proximal Cerebral Arteries Develop Myogenic Responsiveness in Heart Failure via Tumor Necrosis Factor-–Dependent Activation of Sphingosine-1-Phosphate Signaling

Background—Heart failure is associated with neurological deficits, including cognitive dysfunction. However, the molecular mechanisms underlying reduced cerebral blood flow in the early stages of heart failure, particularly when blood pressure is minimally affected, are not known. Methods and Results—Using a myocardial infarction model in mice, we demonstrate a tumor necrosis factor- (TNF)–dependent enhancement of posterior cerebral artery tone that reduces cerebral blood flow before any overt changes in brain structure and function. TNF expression is increased in mouse posterior cerebral artery smooth muscle cells at 6 weeks after myocardial infarction. Coordinately, isolated posterior cerebral arteries display augmented myogenic tone, which can be fully reversed in vitro by the competitive TNF antagonist etanercept. TNF mediates its effect via a sphingosine-1-phosphate (S1P)–dependent mechanism, requiring sphingosine kinase 1 and the S1P2 receptor. In vivo, sphingosine kinase 1 deletion prevents and etanercept (2-week treatment initiated 6 weeks after myocardial infarction) reverses the reduction of cerebral blood flow, without improving cardiac function. Conclusions—Cerebral artery vasoconstriction and decreased cerebral blood flow occur early in an animal model of heart failure; these perturbations are reversed by interrupting TNF/S1P signaling. This signaling pathway may represent a potential therapeutic target to improve cognitive function in heart failure. (Circulation. 2012;126:196-206.) Key Words: cerebrovascular circulation myocardial infarction signal transduction sphingosine kinas