Arachidonic acid-evoked Ca2 + signals promote nitric oxide release and proliferation in human endothelial colony forming cells |
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| Institution: | 1. Laboratory of General Physiology, Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, 27100 Pavia, Italy;2. Department of Cell Biology, Institute of Ophthalmology, University College London, 11-43 Bath Street, EC1V 9EL London, United Kingdom;3. Center for the Study of Myelofibrosis, Biotechnology Research Laboratory, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;4. Department of Pharmaceutical Sciences, Università del Piemonte Orientale “Amedeo Avogadro”, 28100 Novara, Italy;5. Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, 86100 Campobasso, Italy;2. Division of Allergy and Clinical Immunology, Department of Medicine, Brigham and Women''s Hospital, Harvard Medical School, Boston, Massachusetts;1. LUNAM University, Oniris, UPSP 5304 of Animal Pathophysiology and Functional Pharmacology, Atlanpôle La Chantrerie, BP 40706, 44307 Nantes, France;2. LUNAM University, Oniris, INRA UMR U703, PanTHER, Atlanpôle La Chantrerie, BP 40706, 44307 Nantes, France;3. LUNAM University, INSERM, UMR 1087/CNRS 6291 Institut du Thorax, F44007 Nantes, France;4. LUNAM University, CNRS UMR 6214, INSERM U1083, F-49000 Angers, France;5. LUNAM Univsersity, Oniris, UPSP, Sanitary Safety in Biotechnologies of the Reproduction, La Chantrerie, BP 40706, 44307 Nantes, France |
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| 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. |
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