Endothelial calcium machinery and angiogenesis: understanding physiology to interfere with pathology

Endothelial cells (ECs) play a pivotal role in physiological and altered tissue neovascularization. They face multiple morphological, biochemical and functional changes during the different phases of angiogenesis, under the regulation of a great number of proangiogenic and antiangiogenic signals, including soluble and insoluble factors, cell-cell and cell-matrix interactions. ECs mutual contacts (and also interactions with other cell types, such as pericytes and smooth vascular muscle cells), motility, proliferation, apoptosis and differentiation are all calcium-dependent events finely tuned in space and time. Most of the angiogenic-related peptidic factors (VEGF, bFGF and others) promote an increase of cytosolic free calcium concentration in ECs, giving rise to calcium-activated intracellular cascades engaged in the different steps of the angiogenic process. A better knowledge of such signals could allow to set new diagnostic and therapeutical approaches aimed to interfere with altered neovascularization, particularly during cancer progression. This review reports the state of the art about endothelial angiogenic-related calcium signaling and discusses the most attractive perspectives for the future.