Calcium, mitochondria and oxygen sensing in the pulmonary circulation

Abstract

A key event in hypoxic pulmonary vasoconstriction (HPV) is the elevation in smooth muscle intracellular Ca 2+ concentration. However, there is controversy concerning the source of this Ca 2+, the signal transduction pathways involved, and the identity of the oxygen sensor. Although there is wide support for the hypothesis that hypoxia elicits depolarisation via inhibition of K + channels, and thus promotes Ca 2+ entry through L-type channels, a significant number of studies are inconsistent with this mechanism being either the sole or even major means by which Ca 2+ is elevated during HPV. There is strong evidence that intracellular Ca 2+ stores play a critical role, and voltage-independent Ca 2+ entry mechanisms including capacitative Ca 2+ entry (CCE) have also been implicated. There is renewed interest in the role of mitochondria in HPV, both in terms of modulators of Ca 2+homeostasis per se and as oxygen sensors. There is however considerable uncertainty concerning the mechanisms involved in the latter, with proposals for changes in redox couples and both an increase and decrease in mitochondrial production of reactive oxygen species (ROS). In this article we review the evidence for and against involvement of such mechanisms in HPV, and propose a model for the regulation of intracellular [Ca 2+] in pulmonary artery during hypoxia in which the mitochondria play a central role.