Proximal cerebral arteries develop myogenic responsiveness during heart failure via TNFα‐dependent activation of S1P signalling

Heart failure (HF) is associated with neurological deficits and cognitive decline, symptoms that putatively emerge as a result of poor brain perfusion. This investigation seeks to define the molecular mechanisms that underlie reduced cerebral blood flow in the early stages of HF, when blood pressure remains minimally affected. Utilizing a myocardial infarction model in mice, we demonstrate a TNFα‐dependent enhancement of posterior cerebral artery (PCA) myogenic tone, which correlates with reduced cerebral blood flow. Two lines of evidence suggest that TNFα acts by an autocrine/paracrine mechanism: (i) in HF, PCA smooth muscle cell TNFα expression is up‐regulated, and (ii) the HF‐stimulated augmentation of myogenic tone in PCAs is fully reversed by ex vivo treatment with the competitive TNFα antagonist etanercept. TNFα mediates its tone‐enhancing effect via an S1P‐dependent mechanism, requiring sphingosine kinase 1 and the S1P 2 receptor. Our data show that clinically‐silent cerebrovascular dysfunction develops early in this animal model of HF, and leads us to posit that early therapeutic targeting of the TNFα/S1P signalling axis may prevent the neurological deficits that later emerge.