Background:

Subarachnoid hemorrhage (SAH) is a complex stroke subtype where an intracranial bleed precipitates cerebrovascular constriction and ischemia. Current therapeutic strategies fail to consistently improve clinical outcome, presumably because non-selectively curtailing cerebrovascular constriction disrupts the autoregulation of cerebral blood flow. We aim to (i) show that exacerbated myogenic responsiveness drives the enhanced cerebrovascular tone, (ii) identify the underlying signaling components, and (iii) validate new autoregulation-preserving targets for future SAH treatment with a high potential for clinical benefit.

Methods and Results:

Utilizing a mouse model of SAH, we identify a vascular autocrine/paracrine network via tumor necrosis factor α (TNFα), the cystic fibrosis transmembrane conductance regulator (CFTR), and sphingosine-1-phosphate (S1P) that augments myogenic tone in isolated cerebral resistance arteries. We validate the specificity and therapeutic viability of targeting TNFα and S1P₂ receptor subtype signaling in vivo: both interventions (i.e., systemic application of either the TNFα scavenger etanercept or the S1P₂ antagonist JTE013) eliminate the SAH-induced myogenic tone enhancement, but otherwise leave vascular reactivity intact. Consequently, systemic sequestration of TNFα (etanercept) post SAH normalizes cerebral blood flow and mitigates SAH-induced neuronal degeneration and apoptosis.

Conclusions:

Auto- and paracrine microvascular smooth muscle cell TNFα and S1P signaling enhance cerebral artery tone in SAH. We propose that the immediate initiation of anti-TNFa and anti-S1P treatment may improve clinical outcome in the human population by correcting the pathological enhancement of cerebrovascular tone and the reduction in cerebral blood flow without comprimising cerebrovascular autoregulation.