Hypoxic pulmonary vasoconstriction requires connexin 40–mediated endothelial signal conduction
Liming Wang, … , Hermann Kuppe, Wolfgang M. Kuebler
Liming Wang, … , Hermann Kuppe, Wolfgang M. Kuebler
Published October 24, 2012
Citation Information: J Clin Invest. 2012;122(11):4218-4230. https://doi.org/10.1172/JCI59176.
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Research Article

Hypoxic pulmonary vasoconstriction requires connexin 40–mediated endothelial signal conduction

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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Figure 2

Cx40 is required for an intact HPV response.

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Cx40 is required for an intact HPV response. (A) Representative tracings...
(A) Representative tracings of PAP in isolated perfused lungs of Cx40+/+ and Cx40–/– mice obtained during stepwise changes in lung perfusion (Q) at normoxia (21% O2) or hypoxia (1% O2). Note the attenuated HPV response in Cx40–/– mice. (B) Nonlinear regression analysis according to the distensible vessel model yielded representative pressure-flow curves for lungs of Cx40+/+ and Cx40–/– mice at normoxia and hypoxia. The pressure at 0 ml/kg/min flow (Q) reflects left arterial pressure of 2 mmHg, while the slope of the pressure-flow curve at 0 ml/kg/min flow reflects R0. (C) Group data showing acute HPV response, determined as ΔPAP and as R0 10 minutes after hypoxia onset versus normoxia, in untreated isolated perfused lungs of Cx40+/+ and Cx40–/– mice and in lungs of Cx40+/+ mice treated with 18α-glycyrrhetinic acid (GA; 50 μM) or gap2740 (200 μM). (D) Group data (n = 5 lungs each) showing acute HPV response to Ang II (1 μg bolus infusion), determined as ΔPAP and as R0 versus baseline, in untreated isolated perfused lungs of Cx40+/+ and Cx40–/– mice and in lungs of Cx40+/+ mice treated with 18α-glycyrrhetinic acid or gap2740. *P < 0.05 vs. normoxia or baseline control; #P < 0.05 vs. untreated Cx40+/+.