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TNFα modulates spiral modiolar artery tone via regulation of the endogenous sphingosine kinase 1
Author(s) -
Scherer Elias Q.,
Lidington Darcy,
Peter Bernhard Friedrich,
Pitson Stuart,
Arnold Wolfgang,
Pohl Ulrich,
Bolz SteffenSebastian
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a269-c
Subject(s) - sphingosine kinase 1 , sphingosine , vasoconstriction , microbiology and biotechnology , endogeny , sphingosine kinase , medicine , biology , endocrinology , sphingosine 1 phosphate , receptor
The spiral modiolar artery (SMA) is the exclusive supplier of blood to the inner ear, and thus constriction of this artery can cause ischemia‐related inner ear pathologies. We have previously shown that exogenous sphingosine‐1‐phosphate (S1P) induces strong vasoconstriction of the SMA. We proposed: (i) that endogenous S1P generated by the sphingosine kinase 1 (Sk1) plays a key role in SMA tone regulation and (ii) that TNFα(i.e., a relevant pathological mediator) is a potent activator of Sk1. Gerbil SMA were isolated, cannulated (25mmHg transmural pressure) and incubated with plasmids encoding GFP, GFP‐labelled wild‐type Sk1 (Sk1‐GFP) or a catalytically inactive mutant of Sk1 (Sk1 G82D ) under organ culture conditions for 19‐21h. Expression of GFP did not affect vasoconstriction induced by exogenous S1P (EC 50 =115nM, n=5) or the relationship between diameter and Ca 2+ i . Expression of Sk1 G82D (n=7) significantly shifted the diameter/Ca 2+ i relationship to the right. In contrast, incubation with 1nM TNFα (2h, n=6) left‐shifted the curve, an effect that was prevented by expression of Sk1 G82D (n=7) or pretreatment with the TNFα inhibitor Ethanercept (1μg/ml, n=4). TNFα also induced a translocation of Sk1‐GFP from the cytosolic to the plasma membrane compartment, indicating activation of Sk1. We conclude that endogenous Sk1 is a physiological regulator of SMA tone, acting primarily as a modulator of contractile apparatus Ca 2+ sensitivity. This mechanism can be targeted by TNFα, possibly linking several inner ear pathologies to dysfunction of the microcirculation.