The first evidence about the pro-angiogenic role of endothelial Ca2+ signaling dates back to thirty years ago, when Criscuolo and coworkers demonstrated that the tumor-secreted vascular permeability factor, subsequently identified as VEGF by Napoleone Ferrara [156], caused a biphasic increase in [Ca2+]i in several types of endothelial cells, including HUVEC [159]. This evidence concerns the gene VEGFA and neoplasm.