The Role of Sphingosine Kinase 1/Sphingosine-1-Phosphate Pathway in the Myogenic Tone of Posterior Cerebral Arteries

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.

S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

“…Pharmacological inhibition of SPHK1 also suggested a role of SPHK1 in the myogenic response (Lim et al, 2012). In the Lim et al (2012) study, vessels were also incubated with exogenous S1P (1 mM), which as expected increased the basal tone at 20 mmHg, most likely through the activation of S1PR2,3, without affecting the magnitude of the myogenic response in response to pressure.…”

“…These data suggest that SLs produced in the VSMCs exert a vasculoprotective function by resetting vascular tone and BP to a lower-than-normal value in physiologic and pathologic states (Cantalupo et al, 2015). Notably, pressure also increased S1P production in rabbit posterior cerebral arteries (Lim et al, 2012), suggesting the involvement of locally produced S1P in mechano-transduction signaling.…”

“…In the Lim et al (2012) study, vessels were also incubated with exogenous S1P (1 mM), which as expected increased the basal tone at 20 mmHg, most likely through the activation of S1PR2,3, without affecting the magnitude of the myogenic response in response to pressure. This suggests that endogenous, and not exogenous, S1P modulates myogenic tone.…”

Sphingosine-1-Phosphate Evokes Unique Segment-Specific Vasoconstriction of the Renal Microvasculature

“…Studies in hamster gracilis muscle resistance arteries and rabbit posterior cerebral arteries suggest that S1P can be stimulated in response to elevation of transmural pressure. 31,38,42 Therefore, more studies are needed to explore the renal S1P signaling pathway to advance our current knowledge. Collectively, the functional data combined with the Western blot and immunofluorescence data suggest that S1P1 and S1P2 receptors are responsible for S1P-mediated vasoconstriction of the preglomerular microvasculature.…”

Sphingolipid De Novo Biosynthesis: A Rheostat of Cardiovascular Homeostasis

“…Changes in pressure trigger S1P production in rabbit posterior cerebral arteries [57]. Furthermore, elevated levels of S1P in the vascular wall through Sphk1 overexpression [58] or S1P-phosphohydrolase knockdown [59] increase the myogenic tone of resistance arteries, whereas the overexpression of S1P-phosphohydrolase decreases vascular tone in response to pressure, implicating local produced S1P in myogenic tone regulation.…”