Abstract
It has long been known that endothelial Ca2+ signals drive angiogenesis by recruiting multiple Ca2+-sensitive decoders in response to pro-angiogenic cues, such as vascular endothelial growth factor, basic fibroblast growth factor, stromal derived factor-1α and angiopoietins. Recently, it was shown that intracellular Ca2+ signaling also drives vasculogenesis by stimulation proliferation, tube formation and neovessel formation in endothelial progenitor cells. Herein, we survey how growth factors, chemokines and angiogenic modulators use endothelial Ca2+ signaling to regulate angiogenesis and vasculogenesis. The endothelial Ca2+ response to pro-angiogenic cues may adopt different waveforms, ranging from Ca2+ transients or biphasic Ca2+ signals to repetitive Ca2+ oscillations, and is mainly driven by endogenous Ca2+ release through inositol-1,4,5-trisphosphate receptors and by store-operated Ca2+ entry through Orai1 channels. Lysosomal Ca2+ release through nicotinic acid adenine dinucleotide phosphate-gated two-pore channels is, however, emerging as a crucial pro-angiogenic pathway, which sustains intracellular Ca2+ mobilization. Understanding how endothelial Ca2+ signaling regulates angiogenesis and vasculogenesis could shed light on alternative strategies to induce therapeutic angiogenesis or interfere with the aberrant vascularization featuring cancer and intraocular disorders.
Highlights
The vasculature is a highly branched, tree-like, tubular network, which encompasses a system of hierarchically organized arteries, veins and interconnecting capillary beds that is optimized to provide all tissues with crucial nutrients and oxygen and remove their catabolic waste [1]
Vascular development is initiated by mesoderm-derived endothelial progenitor cells (EPC), which migrate into the yolk sac and coalesce to form primitive vascular channels, a process termed vasculogenesis
The Ca2+-dependent decoder of vascular endothelial growth factor (VEGF)-induced intracellular Ca2+ oscillations in myeloid angiogenic cells (MAC) is represented by endothelial nitric oxide (NO) synthase (eNOS) [316,317], it is likely that future investigations reveal additional Ca2+-sensitive effectors
Summary
The vasculature is a highly branched, tree-like, tubular network, which encompasses a system of hierarchically organized arteries, veins and interconnecting capillary beds that is optimized to provide all tissues with crucial nutrients and oxygen and remove their catabolic waste [1]. Growth factors and chemokines induce the angiogenic switch through an increase in [Ca2+]i that stimulates endothelial cell proliferation, adhesion, migration and bidimensional tube formation [16,25,26,27]. Genetic silencing of PLCβ3 impaired proliferation, migration and tubulogenesis in HUVEC grown in the presence of EGM-2 [72], an endothelial growth medium enriched with multiple growth factors It has, been shown that the RTK VEGF receptor 2 (VEGFR2), which is the main signaling VEGF receptor in vascular endothelial cells [24], may recruit PLCβ3 through phosphorylation at serine 537 and 1105 (S537 and S1105) [70]. Ca2+ sequestration in endothelial ER vesicles is impaired by genetic silencing of SERCA2b, but not SERCA3 [48]
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