Hypoxic Pulmonary Vasoconstriction – Invited Article

Abstract

Hypoxic pulmonary vasoconstriction (HPV) is an adaptive mechanism that in the face of localised alveolar hypoxia diverts blood away from poorly ventilated regions of the lung, thereby preserving ventilation/perfusion matching. HPV has been recognised for many years, but although the underlying mechanisms are known to reside within the arteries themselves, their precise nature remains unclear. There is a growing consensus that mitochondria act as the oxygen sensor, and that Ca²⁺ release from ryanodine-sensitive stores and Rho kinase-mediated Ca²⁺ sensitisation are critical for sustained vasoconstriction, though Ca²⁺ entry via both voltage-dependent and/or -independent pathways has also been implicated. There is, however, controversy regarding the signalling pathways that link the oxygen sensor to its effectors, with three main hypotheses. The AMP-activated protein kinase (AMPK) hypothesis proposes that hypoxic inhibition of mitochondrial function increases the AMP/ATP ratio and thus activates AMPK, which in turn mediates cADPR-dependent mobilisation of ryanodine-sensitive sarcoplasmic reticulum Ca²⁺ stores. In contrast the two other hypotheses invoke redox signalling, albeit in mutually incompatible ways. The Redox hypothesis proposes that hypoxia suppresses mitochondrial generation of reactive oxygen species (ROS) and causes the cytosol to become more reduced, with subsequent inhibition of K_V channels, depolarisation and voltage-dependent Ca²⁺ entry. In direct contrast the ROS hypothesis proposes that hypoxia causes an apparently paradoxical increase in mitochondrial ROS generation, and it is this increase in ROS that acts as the signalling moiety. In this article we describe our current understanding of HPV, and evidence in support of these models of oxygen-sensing.