Reactive Oxygen Species and Endothelial Ca(2+) Signaling: Brothers in Arms or Partners in Crime?

An increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) controls virtually all endothelial cell functions and is, therefore, crucial to maintain cardiovascular homeostasis. An aberrant elevation in endothelial can indeed lead to severe cardiovascular disorders. Likewise, moderate amounts of reactive oxygen species (ROS) induce intracellular Ca(2+) signals to regulate vascular functions, while excessive ROS production may exploit dysregulated Ca(2+) dynamics to induce endothelial injury. Herein, we survey how ROS induce endothelial Ca(2+) signals to regulate vascular functions and, vice versa, how aberrant ROS generation may exploit the Ca(2+) handling machinery to promote endothelial dysfunction. ROS elicit endothelial Ca(2+) signals by regulating inositol-1,4,5-trisphosphate receptors, sarco-endoplasmic reticulum Ca(2+)-ATPase 2B, two-pore channels, store-operated Ca(2+) entry (SOCE), and multiple isoforms of transient receptor potential (TRP) channels. ROS-induced endothelial Ca(2+) signals regulate endothelial permeability, angiogenesis, and generation of vasorelaxing mediators and can be exploited to induce therapeutic angiogenesis, rescue neurovascular coupling, and induce cancer regression. However, an increase in endothelial [Ca(2+)](i) induced by aberrant ROS formation may result in endothelial dysfunction, inflammatory diseases, metabolic disorders, and pulmonary artery hypertension. This information could pave the way to design alternative treatments to interfere with the life-threatening interconnection between endothelial ROS and Ca(2+) signaling under multiple pathological conditions.