Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage

BACKGROUND AND PURPOSE—Subarachnoid hemorrhage (SAH) is a complex stroke subtype characterized by an initial brain injury, followed by delayed cerebrovascular constriction and ischemia. Current therapeutic strategies nonselectively curtail exacerbated cerebrovascular constriction, which necessarily...

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Bibliographic Details
Published in:Stroke (1970) 2015-08, Vol.46 (8), p.2260-2270
Main Authors: Yagi, Kenji, Lidington, Darcy, Wan, Hoyee, Fares, Jessica C, Meissner, Anja, Sumiyoshi, Manabu, Ai, Jinglu, Foltz, Warren D, Nedospasov, Sergei A, Offermanns, Stefan, Nagahiro, Shinji, Macdonald, R Loch, Bolz, Steffen-Sebastian
Format: Article
Language:English
Subjects:
Animals
Cerebral Arteries - drug effects
Cerebral Arteries - physiology
Gene Targeting - methods
Lysophospholipids - biosynthesis
Lysophospholipids - deficiency
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - physiology
Organ Culture Techniques
Phenylephrine - administration & dosage
Signal Transduction - drug effects
Signal Transduction - physiology
Sphingosine - analogs & derivatives
Sphingosine - biosynthesis
Sphingosine - deficiency
Subarachnoid Hemorrhage - metabolism
Subarachnoid Hemorrhage - physiopathology
Subarachnoid Hemorrhage - therapy
Tumor Necrosis Factor-alpha - biosynthesis
Tumor Necrosis Factor-alpha - deficiency
Vasoconstriction - drug effects
Vasoconstriction - physiology
Vasomotor System - drug effects
Vasomotor System - physiology
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Summary:BACKGROUND AND PURPOSE—Subarachnoid hemorrhage (SAH) is a complex stroke subtype characterized by an initial brain injury, followed by delayed cerebrovascular constriction and ischemia. Current therapeutic strategies nonselectively curtail exacerbated cerebrovascular constriction, which necessarily disrupts the essential and protective process of cerebral blood flow autoregulation. This study identifies a smooth muscle cell autocrine/paracrine signaling network that augments myogenic tone in a murine model of experimental SAHit links tumor necrosis factor-α (TNFα), the cystic fibrosis transmembrane conductance regulator, and sphingosine-1-phosphate signaling. METHODS—Mouse olfactory cerebral resistance arteries were isolated, cannulated, and pressurized for in vitro vascular reactivity assessments. Cerebral blood flow was measured by speckle flowmetry and magnetic resonance imaging. Standard Western blot, immunohistochemical techniques, and neurobehavioral assessments were also used. RESULTS—We demonstrate that targeting TNFα and sphingosine-1-phosphate signaling in vivo has potential therapeutic application in SAH. Both interventions (1) eliminate the SAH-induced myogenic tone enhancement, but otherwise leave vascular reactivity intact; (2) ameliorate SAH-induced neuronal degeneration and apoptosis; and (3) improve neurobehavioral performance in mice with SAH. Furthermore, TNFα sequestration with etanercept normalizes cerebral perfusion in SAH. CONCLUSIONS—Vascular smooth muscle cell TNFα and sphingosine-1-phosphate signaling significantly enhance cerebral artery tone in SAH; anti-TNFα and anti–sphingosine-1-phosphate treatment may significantly improve clinical outcome.
ISSN:0039-2499
1524-4628
DOI:10.1161/STROKEAHA.114.006365