Oxygen sensing and signal transduction in hypoxic pulmonary vasoconstriction

Abstract

Number 11 in the series "Physiology in respiratory medicine" Edited by R. Naeije, D. Chemla, A. Vonk-Noordegraaf and A.T. Dinh-Xuan Affiliation: Excellence Cluster Cardiopulmonary System, University of Giessen Lung Center, German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, Germany.Correspondence: Norbert Weissmann, Excellence Cluster Cardiopulmonary System, University of Giessen Lung Center, German Center for Lung Research (DZL), Justus-Liebig-University, 35392 Giessen, Germany. E-mail: Norbert.Weissmann@innere.med.uni-giessen.de ABSTRACT Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler-Liljestrand mechanism, is an essential response of the pulmonary vasculature to acute and sustained alveolar hypoxia. During local alveolar hypoxia, HPV matches perfusion to ventilation to maintain optimal arterial oxygenation. In contrast, during global alveolar hypoxia, HPV leads to pulmonary hypertension. The oxygen sensing and signal transduction machinery is located in the pulmonary arterial smooth muscle cells (PASMCs) of the pre-capillary vessels, albeit the physiological response may be modulated in vivo by the endothelium. While factors such as nitric oxide modulate HPV, reactive oxygen species (ROS) have been suggested to act as essential mediators in HPV. ROS may originate from mitochondria and/or NADPH oxidases but the exact oxygen sensing mechanisms, as well as the question of whether increased or decreased ROS cause HPV, are under debate. ROS may induce intracellular calcium increase and subsequent contraction of PASMCs via direct or indirect interactions with protein kinases, phospholipases, sarcoplasmic calcium channels, transient receptor potential channels, voltage-dependent potassium channels and L-type calcium channels, whose relevance may vary under different experimental conditions. Successful identification of factors regulating HPV may allow development of novel therapeutic approaches for conditions of disturbed HPV. @ERSpublications ROS originating from mitochondria and/or NADPH oxidases may initiate HPV but exact signalling mechanisms are unclear http://ow.ly/SkaGC

Hypoxic pulmonary vasoconstriction: clinical implications

“…SOMMER et al [1] have reviewed HPV in this issue of the European Respiratory Journal. The literature is so extensive that another recent comprehensive review contained 2229 references [2].…”

“…The widespread occurrence of HPV throughout the animal kingdom [1] suggests an evolutionary advantage, occurring in the later stages of fetal development in utero. HPV is switched off at birth, but responds in adult life to external (high-altitude) or internal (local hypoventilation) hypoxia.…”

“…HPV clearly has a role to play in the latter third of fetal development in helping to adjust the distribution of the combined ventricular outputs in the most favourable manner for organ growth and development. HPV occurs in almost all vertebrates [1]. How useful or otherwise is its persistence into post-natal life?…”

Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension

“…To this aim, we first examined the effects of vehicle, dasatinib, and imatinib treatment on acute hypoxic pulmonary vasoconstriction (HPV) in vivo, an essential physiological mechanism adapting lung perfusion to regional ventilation that depends critically on the function of the pulmonary endothelium (13). We found that rats treated with dasatinib (10×) exhibited a blunted HPV when compared with rats treated with vehicle, the low dose of dasatinib, or imatinib ( Figure 2A).…”

The ROS controversy in hypoxic pulmonary hypertension revisited

“…Although there is a global consensus amongst scientists that elevation of the intracellular calcium concentration plays a critical role in producing HPV, the precise underlying mechanisms (e.g. nature of the oxygen sensor, direction of changes in reactive oxygen species (ROS) as well as how ROS production affects the activity of calcium channels) and even the cell type involved remain a subject of ongoing debate [2][3][4].Numerous studies have pinpointed the critical implication of ROS in HPV, but controversy remains regarding levels of ROS that mediate HPV [2,5]. Due, at least in part, to the broad range of chemically distinct ROS, their highly reactive nature, as well as differing methods of quantification and models, conflicting results have been reported establishing two partly opposing models.…”