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Stromal cell-derived factor-1α promotes endothelial colony forming cell migration through the Ca2+-dependent activation of the extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase/AKT pathways.

Stromal cell-derived factor-1α promotes endothelial colony forming cell migration through the Ca2+-dependent activation of the extracellular signal-regulated kinase 1/2 and phosphoinositide 3-kinase/AKT pathways.
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Zuccolo E, Di Buduo CA, Lodola F, Orecchioni S, Scarpellino G, Kheder DA, Poletto V, Guerra G, Bertolini F, Balduini A, Rosti V, Moccia F,


Zuccolo E, Di Buduo CA, Lodola F, Orecchioni S, Scarpellino G, Kheder DA, Poletto V, Guerra G, Bertolini F, Balduini A, Rosti V, Moccia F, (click to view)

Zuccolo E, Di Buduo CA, Lodola F, Orecchioni S, Scarpellino G, Kheder DA, Poletto V, Guerra G, Bertolini F, Balduini A, Rosti V, Moccia F,

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Stem cells and development 2017 11 09() doi 10.1089/scd.2017.0114

Abstract

Stromal derived factor-1α (SDF-1α) drives endothelial colony forming cell (ECFC) homing and incorporation within neovessels, thereby restoring tissue perfusion in ischemic tissues and favouring tumor vascularization and metastasis. SDF-1α stimulates ECFC migration by activating the Gi-protein coupled receptor, CXCR4, and then engaging the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway. Sporadic evidence showed that SDF-1α may also act through an increase in intracellular Ca2+ concentration ([Ca2+]i) in bone marrow-derived hematopoietic progenitor cells and fully differentiated endothelial cells. Of note, recent evidence demonstrated that intracellular Ca2+ signals play a key role in controlling the pro-angiogenic activity of ECFCs. The present investigation was, therefore, undertaken to assess whether and how SDF-1α induces ECFC motility by triggering intracellular Ca2+ signals. We found that SDF-1α caused a dose-dependent increase in [Ca2+]i that was inhibited by ADM3100, a selective CXCR4 antagonist. Pharmacological manipulation revealed that the Ca2+ response to [Ca2+]i was shaped by an initial intracellular Ca2+ release through inositol-1,4,5-trisphosphate receptors (InsP3Rs), followed by a sustained phase of extracellular Ca2+ entry through store-operated Ca2+ channels. InsP3-dependent Ca2+ release and store-operated Ca2+ entry (SOCE) were both necessary for SDF-1α-induced extracellular signal-regulated kinases 1/2 (ERK 1/2) and AKT phosphorylation. Finally, SDF-1α employed intracellular Ca2+ signals, ERK 1/2 and PI3K/AKT to promote ECFC migration in vitro and neovessel formation in vivo. These data, therefore, provide the first evidence that SDF-1α induces ECFC migration through the Ca2+-dependent activation of the ERK 1/2 and PI3K/AKT pathways.

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