Journal
STROKE
Volume 46, Issue 8, Pages 2260-2270Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/STROKEAHA.114.006365
Keywords
inflammation; muscle, smooth, vascular; signal transduction; sphingosine kinase-1
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Funding
- Canadian Institutes of Health Research [FRN-119345]
- Physicians Services Incorporated Foundation
- Canadian Foundation for Innovation and Ontario Research Fund [RI-11810]
- Canadian Stroke Network
- Brain Aneurysm Foundation
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Russian Academy of Sciences (Molecular and Cellular Biology)
- Heart and Stroke Foundation of Ontario (HSFO) [G13-0002813, NIA-6581]
- University of Toronto [CI-7432]
- Spatio-Temporal Targeting and Amplification of Radiation
- Grants-in-Aid for Scientific Research [15K10306, 15H04950] Funding Source: KAKEN
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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-alpha (TNF alpha), 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 TNF alpha 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, TNF alpha sequestration with etanercept normalizes cerebral perfusion in SAH. Conclusions-Vascular smooth muscle cell TNF alpha and sphingosine-1-phosphate signaling significantly enhance cerebral artery tone in SAH; anti-TNF alpha and anti-sphingosine-1-phosphate treatment may significantly improve clinical outcome.
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