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

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

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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.

Original languageEnglish
JournalInternational journal of molecular sciences
Issue number24
Publication statusPublished - Dec 17 2019


  • cardiovascular disease
  • G 12/13 proteins
  • hyperreactivity
  • Rho kinase
  • S1P2 receptors
  • sphingosine-1-phosphate
  • vascular smooth muscle
  • α1-adrenoreceptors

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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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. (2019). Sphingosine-1-Phosphate Enhances α1-Adrenergic Vasoconstriction via S1P2-G12/13-ROCK Mediated Signaling. International journal of molecular sciences, 20(24). https://doi.org/10.3390/ijms20246361