Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

Abstract

An increase in intracellular Ca²⁺ concentration ([Ca²⁺]_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 Ca²⁺ signals to regulate vascular functions, while excessive ROS production may exploit dysregulated Ca²⁺ dynamics to induce endothelial injury. Herein, we survey how ROS induce endothelial Ca²⁺ signals to regulate vascular functions and, vice versa, how aberrant ROS generation may exploit the Ca²⁺ handling machinery to promote endothelial dysfunction. ROS elicit endothelial Ca²⁺ signals by regulating inositol-1,4,5-trisphosphate receptors, sarco-endoplasmic reticulum Ca²⁺-ATPase 2B, two-pore channels, store-operated Ca²⁺ entry (SOCE), and multiple isoforms of transient receptor potential (TRP) channels. ROS-induced endothelial Ca²⁺ 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 [Ca²⁺]_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 Ca²⁺ signaling under multiple pathological conditions.

Keywords: Ca2+ signaling; InsP3 receptors; Orai; STIM; endothelial cells; glutathione; hydrogen peroxide; reactive oxygen species; superoxide anion; transient receptor potential channel.