ROS-Dependent Signaling Mechanisms for Hypoxic Ca2+ Responses in Pulmonary Artery Myocytes

Hypoxic exposure causes pulmonary vasoconstriction, which serves as a critical physiologic process that ensures regional alveolar ventilation and pulmonary perfusion in the lungs, but may become an essential pathologic factor leading to pulmonary hypertension. Although the molecular mechanisms underlying hypoxic pulmonary vasoconstriction and associated pulmonary hypertension are uncertain, increasing evidence indicates that hypoxia can result in a significant increase in intracellular reactive oxygen species concentration ([ROS](i)) through the mitochondrial electron-transport chain in pulmonary artery smooth muscle cells (PASMCs). The increased mitochondrial ROS subsequently activate protein kinase C-epsilon (PKC epsilon) and NADPH oxidase (Nox), providing positive mechanisms that further increase [ROS](i). ROS may directly cause extracellular Ca2+ influx by inhibiting voltage-dependent K+ (K-V) channels and opening of store-operated Ca2+ (SOC) channels, as well as intracellular Ca2+ release by activating ryanodine receptors (RyRs), leading to an increase in intracellular Ca2+ concentration ([Ca2+](i)) and associated contraction. In concert with ROS, PKC epsilon may also affect K-V channels, SOC channels, and RyRs, contributing to hypoxic Ca2+ and contractile responses in PASMCs. Antioxid. Redox Signal. 11, 611-623.