Oxygen Sensing in the Pulmonary Circulation
A Fluid State of Affairs
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Since the original description of hypoxic pulmonary vasoconstriction (HPV) by Von Euler and Liljestrand in 1946, where they concluded, “breathing of pure oxygen lowered the pulmonary arterial pressure and oxygen-lack raised it,”1 the precise oxygen-sensing mechanism within the lungs has remained an enigma. Nevertheless, there seems to be some agreement to an overall mechanism for HPV: the primary oxygen sensor is the pulmonary artery smooth muscle cells (PASMC) mitochondrial electron transport chain (ETC); the ETC-produced superoxide/reactive oxygen species (ROS) is the mediator; and redox-sensitive plasma membrane voltage-gated potassium (Kv) channels are the effectors.2 Intriguingly, a similar sensor-mediator-effector model seems to operate in other areas where oxygen is sensed in the body, such as the ductus arteriosus or the carotid body.2 But many controversies exist. Although several groups, including ours, show that acute hypoxia decreases superoxide production from ETC complexes I and III, others find that hypoxia increases superoxide production.2,3 Regardless, most agree that it is the more stable and diffusible hydrogen peroxide (H2O2), produced from superoxide via the mitochondrial MnSOD (manganese superoxide dismutase) that eventually reaches the cell membrane to regulate Kv channels.2,3 However, once again controversy exists. Many groups, including ours, show that decreased levels of H2O2 (a reducing signal) directly inhibits Kv channels (like Kv1.5),2,3 depolarizing the plasma membrane, increasing Ca2+ influx through L-type Ca2+ channels, and causing PASMC contraction2,3 (Kv channels are intrinsically redox sensitive and animals lacking Kv1.5 lack HPV4). Others suggest that increased levels of H2O2 (an oxidative signal) primarily result in an endoplasmic reticulum-mediated calcium release, with K+ channel inhibition as a downstream effect.3 Much has been written about the first controversy, which tends to …