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Open AccessArticle

Sphingosine-1-Phosphate Enhances α1-Adrenergic Vasoconstriction via S1P2–G12/13–ROCK Mediated Signaling

1
Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary
2
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, MD 20892, USA
3
Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany
4
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(24), 6361; https://doi.org/10.3390/ijms20246361
Received: 27 September 2019 / Revised: 4 December 2019 / Accepted: 13 December 2019 / Published: 17 December 2019
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
Sphingosine-1-phosphate (S1P) has been implicated recently in the physiology and pathology of the cardiovascular system including regulation of vascular tone. Pilot experiments showed that the vasoconstrictor effect of S1P was enhanced markedly in the presence of phenylephrine (PE). Based on this observation, we hypothesized that S1P might modulate α1-adrenergic vasoactivity. In murine aortas, a 20-minute exposure to S1P but not to its vehicle increased the Emax and decreased the EC50 of PE-induced contractions indicating a hyperreactivity to α1-adrenergic stimulation. The potentiating effect of S1P disappeared in S1P2 but not in S1P3 receptor-deficient vessels. In addition, smooth muscle specific conditional deletion of G12/13 proteins or pharmacological inhibition of the Rho-associated protein kinase (ROCK) by Y-27632 or fasudil abolished the effect of S1P on α1-adrenergic vasoconstriction. Unexpectedly, PE-induced contractions remained enhanced markedly as late as three hours after S1P-exposure in wild-type (WT) and S1P3 KO but not in S1P2 KO vessels. In conclusion, the S1P–S1P2–G12/13–ROCK signaling pathway appears to have a major influence on α1-adrenergic vasoactivity. This cooperativity might lead to sustained vasoconstriction when increased sympathetic tone is accompanied by increased S1P production as it occurs during acute coronary syndrome and stroke. View Full-Text
Keywords: sphingosine-1-phosphate; α1-adrenoreceptors; vascular smooth muscle; hyperreactivity; S1P2 receptors; G 12/13 proteins; Rho kinase; cardiovascular disease sphingosine-1-phosphate; α1-adrenoreceptors; vascular smooth muscle; hyperreactivity; S1P2 receptors; G 12/13 proteins; Rho kinase; cardiovascular disease
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Panta, C.R.; Ruisanchez, É.; Móré, D.; Dancs, P.T.; Balogh, A.; Fülöp, Á.; Kerék, M.; Proia, R.L.; Offermanns, S.; Tigyi, G.J.; Benyó, Z. Sphingosine-1-Phosphate Enhances α1-Adrenergic Vasoconstriction via S1P2–G12/13–ROCK Mediated Signaling. Int. J. Mol. Sci. 2019, 20, 6361.

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