S ubarachnoid hemorrhage (SAH) affects ≈10 in 100 000 people/y.1 Although SAH accounts for only 5% to 10% of all strokes, it is particularly devastating: half of all SAH patients die within 1 month and half of those who survive will require life-long assistance for daily living (ie, ≈75% of patients die or are seriously debilitated).2,3 The poor clinical outcome can be attributed to the biphasic course of the disease, characterized by an initial hemorrhagic stroke that is frequently followed by delayed cerebral ischemia (DCI) within 4 to 12 days. 4,5 The latter is a primary therapeutic concern when treating SAH, because DCI causes at least half of the morbidity and mortality in SAH. 2The transition from the hemorrhagic insult to secondary ischemia is driven by prominent changes in cerebrovascular reactivity, which compromises cerebral autoregulation 6,7 and evokes angiographic vasospasm (ie, radiographically identifiable arterial narrowing in the proximal cerebrovascular circulation).2,8 Conceptually, both events originate from augmentedBackground 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.

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