Objective
To demonstrate that TNFα, via sphingosine-1-phosphate (S1P) signaling, has the potential to alter cochlear blood flow and thus, cause ischemic hearing loss.
Methods and Results
TNFα induced a pro-constrictive state throughout the cochlear microvasculature, which reduced capillary diameter and cochlear blood flow in vivo. In vitro isolated preparations of the spiral modiolar artery and spiral ligament capillaries confirmed these observations. Antagonizing S1P receptor 2 subtype signaling (1µmol/L JTE013) attenuated the effects of TNFα in all models. TNFα activated Sk1 and induced its translocation to the smooth muscle cell membrane. Expression of a dominant-negative Sk1 mutant (Sk1G82D) eliminated both baseline spiral modiolar artery calcium sensitivity and TNFα effects, while a non-phosphorylatable Sk1 mutant (Sk1S225A) only blocked the effects of TNFα. A small group of etanercept-treated hearing loss patients recovered with a one-phase exponential decay (t½=1.56±0.20 weeks), which matched a kinetic predicted for a vascular origin.
Conclusions
TNFα indeed reduces cochlear blood flow via the activation of vascular S1P signaling. This integrates hearing loss into the family of ischemic microvascular pathologies, with implications for risk stratification, diagnosis and treatment.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.