Title:Manipulating Intracellular Ca2+ Signals to Stimulate Therapeutic Angiogenesis in Cardiovascular Disorders
VOLUME: 19 ISSUE: 9
Author(s):Francesco Moccia*, Roberto Berra-Romani and Vittorio Rosti
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
Keywords:Cardiovascular disorders, therapeutic angiogenesis, endothelial progenitor cells, endothelial colony forming cells,
Ca2+ signalling, TRPC3, store-operated Ca2+ entry, two-pore channel 1.
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.
