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Title

Hypoxic pulmonary vasoconstriction requires connexin 40-mediated endothelial signal conduction

Authors
Wang, Liming
Yin, Jun
Nickles, Hannah T
Ranke, Hannes
Tabuchi, Arata
Hoffmann, Julia
Tabeling, Christoph
Barbosa-Sicard, Eduardo
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Published in Journal of Clinical Investigation. 2012, vol. 122, no. 11, p. 4218-30
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.
Keywords AnimalsAnoxia/genetics/metabolism/pathology/physiopathologyCalcium Channels/metabolismConnexins/genetics/metabolismEndothelium, Vascular/metabolism/pathology/physiopathologyHuman Umbilical Vein Endothelial CellsHumansLung/blood supply/metabolism/pathology/physiopathologyMiceMice, KnockoutMuscle, Smooth/metabolism/pathology/physiopathologyMyocytes, Smooth Muscle/metabolism/pathologyPhospholipases A2, Cytosolic/metabolismPulmonary Artery/metabolism/pathology/physiopathologySignal TransductionVasoconstriction
Identifiers
PMID: 23093775
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Structures
Research groups L'athérosclérose (665)
Mucoviscidose et jonctions GAP (229)
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(ISO format)
WANG, Liming et al. Hypoxic pulmonary vasoconstriction requires connexin 40-mediated endothelial signal conduction. In: Journal of Clinical Investigation, 2012, vol. 122, n° 11, p. 4218-30. https://archive-ouverte.unige.ch/unige:26727

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Deposited on : 2013-03-12

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