Proximal Cerebral Arteries Develop Myogenic Responsiveness in Heart Failure via TNFα-Dependent Activation of S1P Signaling
Background—Heart failure (HF) is associated with neurological deficits, including cognitive dysfunction. However, the molecular mechanisms underlying reduced cerebral blood flow in the early stages of HF, particularly when blood pressure is minimally affected, are not known.
Methods and Results—Utilizing a myocardial infarction (MI) model in mice, we demonstrate a TNFα-dependent enhancement of posterior cerebral artery (PCA) tone, which reduces cerebral blood flow prior to any overt changes in brain structure and function. TNFα expression is increased in mouse PCA smooth muscle cells at 6 weeks post MI. Coordinately, isolated PCAs display augmented myogenic tone, which can be fully reversed in vitro by the competitive TNFα antagonist etanercept. TNFα mediates its effect via an S1P-dependent mechanism, requiring sphingosine kinase 1 and the S1P2 receptor. In vivo, (i) sphingosine kinase 1 deletion prevents and (ii) etanercept (2 week treatment initiated 6 weeks post-MI) restores 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 TNFα/S1P signaling. This signaling pathway may represent a potential therapeutic target to improve cognitive function in heart failure.
- acute myocardial infarction
- cerebrovascular circulation
- signal transduction
- vasomotor tone
- sphingosine kinase 1
- Received April 28, 2011.
- Accepted May 18, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited