Proximal cerebral arteries develop myogenic responsiveness in heart failure via tumor necrosis factor-α-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.


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 S1P(2) 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.
Department of Physiology, Heart and Stroke/Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Ontario, Canada.
Jingli
J
Yang
M Hossein
MH
Noyan-Ashraf
Anja
A
Meissner
Julia
J
Voigtlaender-Bolz
Jeffrey T
JT
Kroetsch
Warren
W
Foltz
David
D
Jaffray
Amita
A
Kapoor
Abdul
A
Momen
Scott P
SP
Heximer
Hangjun
H
Zhang
Matthijs
M
van Eede
R Mark
RM
Henkelman
Stephen G
SG
Matthews
Darcy
D
Lidington
Mansoor
M
Husain
Steffen-Sebastian
SS
Bolz
D000818:Animals; D002536:Cerebral Arteries / Q000473:pathology / Q000503:physiopathology*; D000068800:Etanercept; D006333:Heart Failure / Q000503:physiopathology*; D007074:Immunoglobulin G / Q000494:pharmacology; D008246:Lysophospholipids / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D024510:Muscle Development / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D000099157:Sphingosine Kinase
D000068800:Etanercept; D007074:Immunoglobulin G; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D018124:Receptors, Tumor Necrosis Factor; D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate