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

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