Hypoxic pulmonary vasoconstriction requires connexin 40-mediated endothelial signal conduction

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*

*Corresponding author for this work
92 Citations (Scopus)


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 wildtype 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 Ca 2+ 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.

Original languageEnglish
JournalJournal of Clinical Investigation
Issue number11
Pages (from-to)4218-4230
Number of pages13
Publication statusPublished - 01.11.2012

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)


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