Endothelial Ca(2+) Signaling, Angiogenesis and Vasculogenesis: Just What It Takes to Make a Blood Vessel

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.