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

Cecília R Panta,Richard L Proia,Péter T Dancs,Ágnes Fülöp,Margit Kerék,Andrea Balogh,Gábor J Tigyi,Éva Ruisanchez,Zoltán Benyó,Stefan Offermanns,Dorottya Móré

doi:10.3390/ijms20246361

Abstract

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.

Highlights

In order to dissect the relaxant and constrictor components of the response, we tested the effects of S1P in vessels of endothelial nitric oxide synthase knockout animals, as endothelial NO has been reported to mediate S1P-induced vasorelaxation [9,32]
In order to gain in depth insight into the vasoconstrictor effect, these experiments were repeated with administration of S1P on the resting tone (RT) of the vessels
S1P induced only minor vasoconstriction in both wild-type (WT) (Figure 1C) and endothelial nitric oxide synthase knockout (eNOS KO) (Figure 1D) vessels. These observations indicated that S1P is a weak vasoconstrictor by itself. It can significantly enhance the contractile effect of α1-adrenoreceptor stimulation (Figure 1E)

Summary

Introduction

In spite of the relatively brief history of sphingosine-1-phosphate (S1P) as a biologically active lipid mediator, numerous reports highlight its major regulatory function in embryogenesis [1,2], the immune system and inflammation [3,4,5], the cardiovascular system [6,7,8,9,10], the nervous system [11,12,13], oncogenesis [14,15,16,17], as well as cellular motility and migration [18,19,20,21]. The role of S1P in regulating vascular tone remains controversial because studies conducted in different vascular regions of various animal species have often produced contradictory results [10]. We hypothesized that the variability of S1P effects might be due in part to the absence or presence of other vasoactive mediators. Variable expression S1P receptors, and the coupling of S1P receptors to multiple intracellular signaling pathways, are further complicating factors [6,42]. These factors might be responsible for activating the same receptor subtype, resulting in multiple divergent effects of S1P in different organs and vascular regions [7,9]

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