Proximal cerebral arteries develop myogenic responsiveness in heart failure via tumor necrosis factor-α-dependent activation of sphingosine-1- phosphate signaling

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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-α (TNFα)-dependent enhancement of posterior cerebral artery tone that reduces cerebral blood flow before any overt changes in brain structure and function. TNFα 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 TNFα antagonist etanercept. TNFα 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 TNFα/S1P signaling. This signaling pathway may represent a potential therapeutic target to improve cognitive function in heart failure.


  • Jingli Yang
  • M. Hossein Noyan-Ashraf
  • Anja Meissner
  • Julia Voigtlaender-Bolz
  • Jeffrey T. Kroetsch
  • Warren D. Foltz
  • David Jaffray
  • Amita Kapoor
  • M. Abdul Momen
  • Scott P. Heximer
  • Hangjun Zhang
  • Matthijs Van Eede
  • R. Mark Henkelman
  • Stephen G. Matthews
  • Darcy Lidington
  • Mansoor Husain
  • Steffen Sebastian Bolz
Externa organisationer
  • University of Toronto
  • Princess Margaret Hospital University of Toronto
  • Toronto General Hospital


Sidor (från-till)196-206
Antal sidor11
Utgåva nummer2
StatusPublished - 2012 jul 10
Peer review utfördJa
Externt publiceradJa