FIGURE 2.

Oxygen sensing in PASMC in health and PAH. (A). O₂ detection in PASMC is enabled by the redox-sensitive NDUFS2 in ETC Complex I. NDUFS2 generates ROS during normoxia, creating a relatively oxidized state, whilst in hypoxia, NDUFS2 produces fewer radicals, creating a state of reduction. During normoxia, disulfide bridges in NDUFS2 are oxidized in support of ROS production and SOD2 converts O₂ ⁻ to diffusible H₂O₂ for cytosolic export. H₂O₂ oxidizes redox-sensitive, voltage-gated, K⁺ channels, increasing their open state probability and maintaining tonic K⁺ egression, thereby hyperpolarizing the PASMC membrane potential and inactivating voltage-dependent calcium channels. This favours a state of normoxic relaxation. (B). Epigenetic methylation of the SOD2 gene in PAH by DNMTs reduces SOD2 expression and decreases normoxic production of H₂O_2. The resulting reduced redox state chemically reduces K⁺ channel disulfide bridges, inhibiting K⁺ channel opening and depolarizing the PASMC. As a result, voltage-dependent L-type Ca²⁺ channels (Ca_L) are activated, increasing cytoplasmic Ca²⁺ which leads to vasoconstriction. Changes in redox state and cytosolic calcium also induce calcium/calmodulin (CaM)-dependent activation of myosin light chain kinase (MLCK), which creates a more sustained form of vasoconstriction. O₂ ⁻ also activates ROCK through RhoA, promoting Ca²⁺ sensitization. Abbreviations: Ca_L—L-type calcium channel; CaM—Calmodulin; DNMT—DNA methyltransferases; ETC—Electron transport chain; HIF-1α—Hypoxia-inducible factor 1α; KCNK4—Potassium channel subfamily K member four; Kv—Voltage-gated potassium channel; MCLK—Myosin light chain kinase; MLCP—Myosin light chain phosphatase; NDUFS2—NADH dehydrogenase [ubiquinone] iron-sulfur protein 2; RhoA - Ras homolog family member A; ROCK—Rho kinase; SOD2—Superoxide dismutase 2; ROS—Reactive oxygen species.