Abstract
AimsThe goal of the current study was to determine whether the sphingosine kinase 1 (SK1)/sphingosine-1-phosphate (S1P) pathway is involved in myogenic vasoconstriction under normal physiological conditions. In the present study, we assessed whether endogenous S1P generated by pressure participates in myogenic vasoconstriction and which signaling pathways are involved in SK1/S1P-induced myogenic response under normal physiological conditions.Methods and ResultsWe measured pressure-induced myogenic response, Ca2+ concentration, and 20 kDa myosin light chain phosphorylation (MLC20) in rabbit posterior cerebral arteries (PCAs). SK1 was expressed and activated by elevated transmural pressure in rabbit PCAs. Translocation of SK1 by pressure elevation was blocked in the absence of external Ca2+ and in the presence of mechanosensitive ion channel and voltage-sensitive Ca2+ channel blockers. Pressure-induced myogenic tone was inhibited in rabbit PCAs treated with sphingosine kinase inhibitor (SKI), but was augmented by treatment with NaF, which is an inhibitor of sphingosine-1-phosphate phosphohydrolase. Exogenous S1P further augmented pressure-induced myogenic responses. Pressure induced an increase in Ca2+ concentration leading to the development of myogenic tone, which was inhibited by SKI. Exogenous S1P further increased the pressure-induced increased Ca2+ concentration and myogenic tone, but SKI had no effect. Pressure- and exogenous S1P-induced myogenic tone was inhibited by pre-treatment with the Rho kinase inhibitor and NADPH oxidase inhibitors. Pressure- and exogenous S1P-induced myogenic tone were inhibited by pre-treatment with S1P receptor blockers, W146 (S1P1), JTE013 (S1P2), and CAY10444 (S1P3). MLC20 phosphorylation was increased when the transmural pressure was raised from 40 to 80 mmHg and exogenous S1P further increased MLC20 phosphorylation. The pressure-induced increase of MLC20 phosphorylation was inhibited by pre-treatment of arteries with SKI.ConclusionsOur results suggest that the SK1/S1P pathway may play an important role in pressure-induced myogenic responses in rabbit PCAs under normal physiological conditions.
Highlights
The myogenic response is an intrinsic vascular response characterized by vasoconstriction in response to an increase in intravascular pressure and vasodilation in response to a decrease in intravascular pressure [1]
Our results suggest that the sphingosine kinase 1 (SK1)/S1P pathway may play an important role in pressure-induced myogenic responses in rabbit posterior cerebral arteries (PCAs) under normal physiological conditions
It was reported that myogenic vasoconstriction in response to increased transmural pressure was significantly reduced in resistance arteries transfected with sphingosine-1phosphate phosphohydrolase 1 (SPP1), a S1P-degrading enzyme [14]
Summary
The myogenic response is an intrinsic vascular response characterized by vasoconstriction in response to an increase in intravascular pressure and vasodilation in response to a decrease in intravascular pressure [1]. Arterial myogenic tone plays an important role in establishing ambient vascular tone and autoregulating blood flow in the resistance vasculature, especially in cerebral circulation [2,3,4], because cerebral arteries are not responsive to the sympathetic nerves surrounding them [5]. It was reported that myogenic vasoconstriction in response to increased transmural pressure was significantly reduced in resistance arteries transfected with sphingosine-1phosphate phosphohydrolase 1 (SPP1), a S1P-degrading enzyme [14]. Taken together, these results suggest that SK1 and its product, S1P, may be involved in the pressure-induced signaling cascade leading to myogenic vasoconstriction. Whether SK1/S1P contributes to pressure-induced myogenic responses under normal physiological conditions is unknown
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