Figure 1. Signalling in hypoxic pulmonary vasoconstriction.

Hypoxia increases production at mitochondrial complex III of reactive oxygen species (ROS), which are released into the mitochondrial intermembrane space. ROS signals (superoxide and H₂O₂) can move from the intermembrane space to the cytosol where the superoxide is converted to H₂O₂. H₂O₂ can then activate many downstream signalling pathways. H₂O₂ can activate phospholipase C (PLC) leading to production of inositol 1,4,5‐trisphosphate (IP₃) and diacylglycerol (DAG) from phosphatidylinositol bisphosphate (PIP₂). IP₃ activates IP₃ receptors resulting in Ca²⁺ release from the sarcoplasmic reticulum (SR) and DAG activates receptor‐operated Ca²⁺ channels (ROCC). H₂O₂ also directly activates ryanodine receptors (RyR) by oxidizing cysteine residues, leading the Ca²⁺ release from SR. Release of Ca²⁺ from the SR causes store depletion, which activates Ca²⁺ entry via activation of calcium release‐activated Ca²⁺ (CRAC) channels. H₂O₂ also inhibits K_V channels, which increases the membrane potential (E _m) and opens voltage‐dependent Ca²⁺ channels (VDCC). Together, the increased intracellular Ca²⁺ concentration ([Ca²⁺]_i) causes Ca²⁺ to bind calmodulin (CaM) and activate myosin light chain kinase (MLCK), which phosphorylates myosin (MLC) and leads to contraction of pulmonary arterial smooth muscle cells (PASMC).