Arachidonic acid-evoked Ca2+ signals promote nitric oxide release and proliferation in human endothelial colony forming cells

Estella Zuccolo, Silvia Dragoni, Valentina Poletto, Paolo Catarsi, Daniele Guido, Alessandra Rappa, Marta Reforgiato, Francesco Lodola, Dmitry Lim, Vittorio Rosti, Germano Guerra, Francesco Moccia

Research output: Contribution to journalArticlepeer-review

Abstract

Arachidonic acid (AA) stimulates endothelial cell (EC) proliferation through an increase in intracellular Ca2+ concentration ([Ca2+]i), that, in turn, promotes nitric oxide (NO) release. AA-evoked Ca2+ signals are mainly mediated by Transient Receptor Potential Vanilloid 4 (TRPV4) channels. Circulating endothelial colony forming cells (ECFCs) represent the only established precursors of ECs. In the present study, we, therefore, sought to elucidate whether AA promotes human ECFC (hECFC) proliferation through an increase in [Ca2+]i and the following activation of the endothelial NO synthase (eNOS). AA induced a dose-dependent [Ca2+]i raise that was mimicked by its non-metabolizable analogue eicosatetraynoic acid. AA-evoked Ca2+ signals required both intracellular Ca2+ release and external Ca2+ inflow. AA-induced Ca2+ release was mediated by inositol-1,4,5-trisphosphate receptors from the endoplasmic reticulum and by two pore channel 1 from the acidic stores of the endolysosomal system. AA-evoked Ca2+ entry was, in turn, mediated by TRPV4, while it did not involve store-operated Ca2+ entry. Moreover, AA caused an increase in NO levels which was blocked by preventing the concomitant increase in [Ca2+]i and by inhibiting eNOS activity with NG-nitro-l-arginine methyl ester (l-NAME). Finally, AA per se did not stimulate hECFC growth, but potentiated growth factors-induced hECFC proliferation in a Ca2+- and NO-dependent manner. Therefore, AA-evoked Ca2+ signals emerge as an additional target to prevent cancer vascularisation, which may be sustained by ECFC recruitment.
Original languageEnglish
Pages (from-to)159-171
Number of pages13
JournalVascular pharmacology
Volume87
DOIs
Publication statusPublished - 12 Sept 2016

Keywords

  • Endothelial colony forming cells
  • Arachidonic acid
  • Ca2 +
  • TRPV4
  • Nitric oxide
  • Proliferation

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