Sphingosylphosphorylcholine potentiates vasoreactivity and voltage-gated Ca2+ entry via NOX1 and reactive oxygen species

Yasin Shaifta, Vladimir A. Snetkov, Jesus Prieto-Lloret, Greg A. Knock, Sergey V. Smirnov, Philip I. Aaronson, Jeremy P. T. Ward

Research output: Contribution to journalArticle

13 Citations (Scopus)
136 Downloads (Pure)

Abstract

AIMS: Sphingosylphosphorylcholine (SPC) elicits vasoconstriction at micromolar concentrations. At lower concentrations (≤1 µmol/l) however it does not constrict intrapulmonary arteries (IPA), but strongly potentiates vasoreactivity. Our aim was to determine whether this also occurs in a systemic artery and to delineate the signalling pathway.
METHODS AND RESULTS: Rat mesenteric arteries and IPA mounted on a myograph were challenged with ∼25 mmol/l [K+] to induce a small vasoconstriction. SPC (1 µmol/l) dramatically potentiated this constriction in all arteries by ∼400%. The potentiation was greatly suppressed or abolished by inhibition of PLC (U73122), PKCϵ (inhibitory peptide), Src (PP2), and NADPH oxidase (VAS2870), and by Tempol (superoxide scavenger), but not by inhibition of Rho kinase (Y27632). Potentiation was lost in mesenteric arteries from p47phox -/- but not NOX2-/- mice. The intracellular superoxide generator LY83583 mimicked the effect of SPC. SPC elevated reactive oxygen species (ROS) in vascular smooth muscle cells, and this was blocked by PP2, VAS2870 and siRNA knockdown of PKCϵ. SPC (1 µmol/l) significantly reduced the EC50 for U46619-induced vasoconstriction, an action ablated by Tempol. In patch-clamped mesenteric artery cells SPC (200 nmol/l) enhanced Ba2+ current through L-type Ca2+ channels, an action abolished by Tempol but mimicked by LY83583.
CONCLUSION: Our results suggest that low concentrations of SPC activate a PLC-coupled and NOX1-mediated increase in ROS, with consequent enhancement of voltage-gated Ca2+ entry and thus vasoreactivity. We speculate that this pathway is not specific for SPC, but may also contribute to vasoconstriction elicited by other GPCR and PLC-coupled agonists.
Original languageEnglish
Pages (from-to)121-130
JournalCardiovascular Research
Early online date6 Feb 2015
DOIs
Publication statusPublished - 1 Apr 2015

Keywords

  • Calcium channels
  • smooth muscle
  • artery
  • Reactive Oxygen Species

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