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Cardiovascular Research 2006 70(1):79-87; doi:10.1016/j.cardiores.2006.01.011
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Copyright © 2006, European Society of Cardiology

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

Elias Q. Scherera,b,*, Darcy Lidingtonb, Elmar Oestreichera, Wolfgang Arnolda, Ulrich Pohlb and Steffen-Sebastian Bolzb

aENT-Department, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany
bInstitute of Physiology, Ludwig-Maximilians University, Munich, Germany

* Corresponding author. ENT-Department, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany. Tel.: +49 89 41402392; fax: +49 89 41404952. Email address: E.q.scherer{at}lrz.tum.de

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-1-phosphate (S1P), 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, S1P phosphohydrolase and three S1P receptors (S1P1–3) were detected in the SMA. S1P induced dose-dependent vasoconstriction of the SMA (EC50=115nmol/L), and enhanced the apparent Ca2+-sensitivity of the contractile apparatus. Noradrenaline did not elicit vasoconstriction. The Rho kinase inhibitor Y27632 (1µmol/L) reversed S1P-induced vasoconstriction and the S1P-mediated enhancement of Ca2+-sensitivity. RhoA was observed to translocate to the plasma membrane in response to stimulation with 30µmol/L S1P.

Conclusion We conclude that all key signalling pathway constituents are present at the mRNA level for S1P to act as an endogenous regulator of SMA tone. S1P stimulates potent, RhoA/Rho kinase-dependent SMA vasoconstriction and Ca2+ sensitization. The high sensitivity to S1P suggests that SMA vasoconstriction is likely to occur under pathological conditions that increase intramural S1P 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 S1P bioavailability and the S1P receptors.

KEYWORDS Ca2+-sensitivity; Cochlear blood flow; Rho kinase; RhoA; Sudden hearing loss; Vascular smooth muscle

Time for primary review 26 days


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