Sounding the alarm on hypoxia
Hypoxic pulmonary vasoconstriction (HPV) is a physiological mechanism by which the pulmonary arteries redirect blood flow from a hypoxic region of the lungs to a region that is oxygen rich. Here, Wang et al. used real-time fluorescence imaging in mouse capillaries and arterioles to measure changes in electrical potential of the endothelium in response to hypoxia. Changes in membrane potential are used to propagate changes in oxygen tension to the arterioles. Wang and colleagues found that the gap junction protein connexin 40 propagates a low-oxygen signal that cause the vessels to contract. These results suggest that connexin 40 is a potential target in the treatment of chronic hypoxic lung disease.
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Citation Information: J Clin Invest. 2012;122(11):4218-4230. https://doi.org/10.1172/JCI59176.
Abstract
Hypoxic pulmonary vasoconstriction (HPV) is a physiological mechanism by which pulmonary arteries constrict in hypoxic lung areas in order to redirect blood flow to areas with greater oxygen supply. Both oxygen sensing and the contractile response are thought to be intrinsic to pulmonary arterial smooth muscle cells. Here we speculated that the ideal site for oxygen sensing might instead be at the alveolocapillary level, with subsequent retrograde propagation to upstream arterioles via connexin 40 (Cx40) endothelial gap junctions. HPV was largely attenuated by Cx40-specific and nonspecific gap junction uncouplers in the lungs of wild-type mice and in lungs from mice lacking Cx40 (Cx40–/–). In vivo, hypoxemia was more severe in Cx40–/– mice than in wild-type mice. Real-time fluorescence imaging revealed that hypoxia caused endothelial membrane depolarization in alveolar capillaries that propagated to upstream arterioles in wild-type, but not Cx40–/–, mice. Transformation of endothelial depolarization into vasoconstriction involved endothelial voltage-dependent α1G subtype Ca2+ channels, cytosolic phospholipase A2, and epoxyeicosatrienoic acids. Based on these data, we propose that HPV originates at the alveolocapillary level, from which the hypoxic signal is propagated as endothelial membrane depolarization to upstream arterioles in a Cx40-dependent manner.
Authors
Liming Wang, Jun Yin, Hannah T. Nickles, Hannes Ranke, Arata Tabuchi, Julia Hoffmann, Christoph Tabeling, Eduardo Barbosa-Sicard, Marc Chanson, Brenda R. Kwak, Hee-Sup Shin, Songwei Wu, Brant E. Isakson, Martin Witzenrath, Cor de Wit, Ingrid Fleming, Hermann Kuppe, Wolfgang M. Kuebler
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