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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift


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 SAH: it 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.


  • Kenji Yagi
  • Darcy Lidington
  • Hoyee Wan
  • Jessica C. Fares
  • Anja Meissner
  • Manabu Sumiyoshi
  • Jinglu Ai
  • Warren D. Foltz
  • Sergei A. Nedospasov
  • Stefan Offermanns
  • Shinji Nagahiro
  • R. Loch Macdonald
  • Steffen Sebastian Bolz
Externa organisationer
  • University of Toronto


Sidor (från-till)2260-2270
Antal sidor11
TidskriftStroke; a journal of cerebral circulation
Utgåva nummer8
StatusPublished - 2015 aug 1
Peer review utfördJa
Externt publiceradJa