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Manipulating Intracellular Ca2+ Signals to Stimulate Therapeutic Angiogenesis in Cardiovascular Disorders

[ Vol. 19 , Issue. 9 ]

Author(s):

Francesco Moccia*, Roberto Berra-Romani and Vittorio Rosti   Pages 686 - 699 ( 14 )

Abstract:


Endothelial progenitor cells (EPCs) are mobilized in peripheral blood to rescue blood perfusion in ischemic tissues. Several approaches were, therefore, designed to inject autologous EPCs and induce therapeutic angiogenesis in patients affected by cardiovascular disorders. Endothelial colony forming cells (ECFCs) represent the only truly endothelial precursors and are regarded as the most suitable substrate for cell based therapy of ischemic diseases. Intracellular Ca2+ signalling drives ECFC proliferation, migration, homing and neovessel formation. Vascular endothelial growth factor (VEGF) triggers repetitive oscillations in intracellular Ca2+ concentration ([Ca2+]i) in peripheral blood- and umbilical cord blood-derived ECFCs by initiating a dynamic interplay between inositol-1,4,5-trisphosphate (InsP3)-dependent Ca2+ release and store-operated Ca2+ entry (SOCE). SOCE, in turn, is mediated by Stim1, Orai1 and Transient Receptor Potential (TRP) Canonical 1 (TRPC1). Intriguingly, intracellular Ca2+ oscillations are triggered by TRPC3 in umbilical cord blood-derived ECFCs, which display higher proliferative potential. Additionally, stromal cell-derived factor-1α (SDF-1α) triggers a biphasic increase in [Ca2+]i in ECFCs which is mediated by InsP3 receptors (InsP3Rs) and SOCE. Finally, arachidonic acid (AA) and nicotinic acid adenine dinucleotide phosphate (NAADP) stimulate ECFC proliferation by stimulating two-pore channel 1 (TPC1), thereby promoting Ca2+ release from the endolysosomal Ca2+ compartment. AA-evoked Ca2+ signals are further supported by InsP3Rs and TRP Vanilloid 4 (TRPV4). In this article, we describe how genetic manipulation of the Ca2+ toolkit (i.e. TRPC3, SOCE, TPC1) endowed to circulating ECFCs could rejuvenate or restore their reparative phenotype for therapeutic angiogenesis purposes.

Keywords:

Cardiovascular disorders, therapeutic angiogenesis, endothelial progenitor cells, endothelial colony forming cells, Ca2+ signalling, TRPC3, store-operated Ca2+ entry, two-pore channel 1.

Affiliation:

Laboratory of General Physiology, Department of Biology and Biotechnology, "L. Spallanzani", University of Pavia, Pavia, School of Medicine, Department of Biomedicine, Benemerita Universidad Autonoma de Puebla, Puebla, Center for the Study of Myelofibrosis, Laboratory of Biochemistry, Biotechnology and Advanced Diagnosis, IRCCS Policlinico San Matteo Foundation, Pavia

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