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-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 (S1P(1-3)) were detected in the SMA. S1P induced dose-dependent vasoconstriction of the SMA (EC50 = 115 nmol/L), and enhanced the apparent Ca2+-sensitivity of the contractile apparatus. Noradrenaline did not elicit vasoconstriction. The Rho kinase inhibitor Y27632 (1 micromol/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 30 micromol/L S1P.


CONCLUSIONS
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.
Scherer
Elias Q
EQ
ENT-Department, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany. E.q.scherer@lrz.tum.de
Lidington
Darcy
D
Oestreicher
Elmar
E
Arnold
Wolfgang
W
Pohl
Ulrich
U
Bolz
Steffen-Sebastian
SS
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001158:Arteries; D001692:Biological Transport; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007758:Ear, Inner / Q000098:blood supply*; D004730:Endothelium, Vascular / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D005849:Gerbillinae; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008246:Lysophospholipids / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D049349:Receptors, Lysosphingolipid / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099157:Sphingosine Kinase
D000577:Amides; D002118:Calcium; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011725:Pyridines; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D014662:Vasoconstrictor Agents; D020741:rho GTP-Binding Proteins; D000099157:Sphingosine Kinase; C108830:Y 27632; C060506:sphingosine 1-phosphate