Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage
(2015) In Stroke: a journal of cerebral circulation 46(8). p.2260-2270- Abstract
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,... (More)
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.
(Less)
- author
- publishing date
- 2015-08-01
- type
- Contribution to journal
- publication status
- published
- keywords
- inflammation, muscle, smooth, vascular, signal transduction, sphingosine kinase-1
- in
- Stroke: a journal of cerebral circulation
- volume
- 46
- issue
- 8
- pages
- 11 pages
- publisher
- American Heart Association
- external identifiers
-
- pmid:26138121
- scopus:84944683502
- ISSN
- 1524-4628
- DOI
- 10.1161/STROKEAHA.114.006365
- language
- English
- LU publication?
- no
- id
- e21eff20-b959-4671-80d8-3ec588d9fbb2
- date added to LUP
- 2017-05-23 22:23:14
- date last changed
- 2024-04-14 11:22:49
@article{e21eff20-b959-4671-80d8-3ec588d9fbb2,
abstract = {{<p>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.</p><p>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.</p><p>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.</p><p>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.</p>}},
author = {{Yagi, Kenji and Lidington, Darcy and Wan, Hoyee and Fares, Jessica C. and Meissner, Anja and Sumiyoshi, Manabu and Ai, Jinglu and Foltz, Warren D. and Nedospasov, Sergei A. and Offermanns, Stefan and Nagahiro, Shinji and Macdonald, R. Loch and Bolz, Steffen Sebastian}},
issn = {{1524-4628}},
keywords = {{inflammation; muscle, smooth, vascular; signal transduction; sphingosine kinase-1}},
language = {{eng}},
month = {{08}},
number = {{8}},
pages = {{2260--2270}},
publisher = {{American Heart Association}},
series = {{Stroke: a journal of cerebral circulation}},
title = {{Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage}},
url = {{http://dx.doi.org/10.1161/STROKEAHA.114.006365}},
doi = {{10.1161/STROKEAHA.114.006365}},
volume = {{46}},
year = {{2015}},
}