Fig. 5. Integration of present findings into current concepts of oxygen sensing and HPV in the murine lung.

Acute HPV depends on a central oxygen sensor within the mitochondrial respiratory chain. Hypoxia induces mitochondrial membrane hyperpolarization, an increase in mitochondrial superoxide release, and subsequent inhibition of cellular potassium channels (K_V), which leads to cellular membrane depolarization and activation of voltage-gated calcium channels. This sequence of events results in intracellular calcium increase and HPV. AOX prevents HPV in mouse PASMC by preventing mitochondrial ROS production and release. This places mitochondria and electron flux through the mitochondrial respiratory chain at the top level in the hierarchy of oxygen sensing and signaling controlling HPV. ADP, adenosine diphosphate; FAD, flavin adenine dinucleotide.