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It has long been known that endothelial Ca 2+ signals drive angiogenesis by recruiting multiple Ca 2+ -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 Ca 2+ 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 Ca 2+ signaling to regulate angiogenesis and vasculogenesis. The endothelial Ca 2+ response to pro-angiogenic cues may adopt different waveforms, ranging from Ca 2+ transients or biphasic Ca 2+ signals to repetitive Ca 2+ oscillations, and is mainly driven by endogenous Ca 2+ release through inositol-1,4,5-trisphosphate receptors and by store-operated Ca 2+ entry through Orai1 channels. Lysosomal Ca 2+ release through nicotinic acid adenine dinucleotide phosphate-gated two-pore channels is, however, emerging as a crucial pro-angiogenic pathway, which sustains intracellular Ca 2+ mobilization. Understanding how endothelial Ca 2+ 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.

Endothelial Ca2+ Signaling, Angiogenesis and Vasculogenesis: just What It Takes to Make a Blood Vessel