Sphingosine-1-phosphate modulates spiral modiolar artery tone: A potential role in vascular-based inner ear pathologies?

Objective: The mechanisms regulating spiral modiolar artery (SMA) tone are not known, yet their characterization is pivotal for understanding inner ear blood flow regulation. Sphingosine-I-phosphate (S I P), known to stimulate vasoconstriction in several vascular beds, is a candidate regulator of SMA tone with potential pathophysiological relevance. Methods: Gerbil SMAs were isolated, cannulated and pressurized (30 mm Hg transmural) for experimentation under near-in vivo conditions. For functional experiments, vascular diameter and intracellular Ca2+ were simultaneously measured. Standard RT-PCR and immunohistochemical techniques were also employed. Results: mRNA transcripts encoding sphingosine kinase, SIP phosphohydrolase and three SIP receptors (SIP1-3) were detected in the SMA. SIP induced dose-dependent vasoconstriction of the SMA (EC50 = 115 nmol/L), and enhanced the apparent Ca(2+)sensitivity of the contractile apparatus. Noradrenaline did not elicit vasoconstriction. The Rho kinase inhibitor Y27632 (1 mu mol/L) reversed SIP-induced vasoconstriction and the SIP-mediated enhancement of Ca2+-sensitivity. RhoA was observed to translocate to the plasma membrane in response to stimulation with 30 mu mol/L SIP. Conclusion: We conclude that all key signalling pathway constituents are present at the mRNA level for SIP to act as an endogenous regulator of SMA tone. SIP stimulates potent, RhoA/Rho kinase-dependent SMA vasoconstriction And Ca2+ sensitization. The high sensitivity to SIP suggests that SMA vasoconstriction is likely to occur under pathological conditions that increase intramural SIP concentrations (i.e., inflammation). From a clinical perspective, the present study identifies new potential therapeutic targets for the treatment of vascular-based, stroke-like inner ear pathologies: the enzymes responsible for SIP bioavailability and the SIP receptors. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.