Hypoxic pulmonary vasoconstriction (HPV) occurs during both fetal and postnatal development and plays a critical role in matching regional alveolar perfusion with ventilation in humans and animals. HPV also contributes significantly to the development of
pulmonary hypertension. Although the molecular mechanisms of HPV and
pulmonary hypertension remain incompletely understood, increasing evidence demonstrates that
hypoxia induces an elevated intracellular
reactive oxygen species concentration ([ROS]i) in pulmonary artery smooth muscle cells (PASMCs). The increased [ROS]i is attributed to the mitochondrial electron transport chain (ETC) and plasmalemmal
NADPH oxidase (NOX); however, the mitochondrial ETC is a primary source for the elevated [ROS]i. Our studies reveal that mitochondrial ROS can specifically increase the activity of
protein kinase C-ε, activate NOX, and then induce more ROS production (i.e., ROS-induced ROS production, RIRP). Mitochondrial ROS production is principally mediated by
Rieske iron-sulfur protein (RISP) at the
complex III. The increased [ROS]i causes an elevation of intracellular Ca2+ concentration ([Ca2+]i), thereby leading to HPV and associated
pulmonary hypertension.
Ryanodine receptor-2 (
RyR2)/Ca2+ release channel on the sarcoplasmic reticulum (SR) serves as a most valuable player in the elevated [Ca2+]i. Our recent data indicate that RyR2-induced Ca2+ release can enhance RISP-mediated increase in mitochondrial ROS concentration ([ROS]mito), and that the mitochondrial Ca2+ uniporter is involved in elevating [ROS]mito. Based on the existing reports and our unpublished data, we conclude that the cross talk between [ROS]mito and [Ca2+]i, that is RISP-dependent mitochondrial ROS-induced RyR2-mediated SR Ca2+ release (ROS-induced Ca2+ release, RICR) and RyR2-mediated SR Ca2+ release-induced RISP-dependent mitochondrial ROS production (Ca2+-induced ROS production, CIRP), may form a positive reciprocal loop in mediating HPV and also possibly
pulmonary hypertension.