Redox-Based Mechanisms of O₂ Sensing in Hypoxic Pulmonary Vasoconstriction; Where Are We Now?

Hypoxic pulmonary vasoconstriction (HPV) is a rapid and reversible constrictor response of the pulmonary vasculature, and especially its small muscular precapillary arteries, which is initiated by episodes of local alveolar hypoxia. Acting as a protective homeostatic vasomotor mechanism, HPV enables maximal gas exchange by diverting blood from poorly ventilated alveoli in to those rich in oxygen, thereby optimizing oxygen uptake and the ventilation-perfusion (V/Q) ratio so as to maintain the arterial oxygen partial pressure (PaO2) within the physiological range. HPV is an intrinsic mechanism of pulmonary artery smooth muscle cells (PASMC), and requires an O2 sensor which acts through mediator(s) to trigger effector mechanisms within these cells to evoke constriction. Whereas HPV effector mechanisms are reasonably well-defined, the nature of the O2 sensor and mediators remain in dispute. The three most comprehensive models of O2 sensing in HPV share a focus on the concept that hypoxia activates effector mechanisms by inducing a change in the PASMC cytoplasmic redox state. According to the Redox Theory, first proposed by Kenneth Weir and Stephen Archer in 1995, hypoxia inhibits mitochondrial production of reactive oxygen species (ROS), thereby causing the cytoplasm to become more reduced. This inhibits ongoing vasorelaxation maintained by the opening of voltage-gated K+ channels. In contrast, according to the Mitochondrial ROS hypothesis, introduced by Paul Schumacker and Naveen Chandel in 2001, hypoxia increases mitochondrial ROS production, causing an oxidizing shift in the cytoplasmic redox poise which activate several vasoconstricting pathways. In a third scenario, developed by Michael Wolin and Sachin Gupte, hypoxia evokes contraction by causing a fall in H2O2 production by NADPH oxidase, and by activating the pentose phosphate pathway. These effects inhibit basal vasorelaxation maintained by the guanylate cyclase and protein kinase G and also stimulate vasoconstricting mechanisms. In this comprehensive review, we summarize the key studies contributing to the development of these proposals and then subject the evidence supporting them to critical appraisal, based in part on how well they accord with the wider literature and recent developments in our understanding of how cells shape and deploy redox mechanisms in order to regulate cell function.