Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews...
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • Allergy (Apr 2019)
    • Biology of familial cancer predisposition syndromes (Feb 2019)
    • Mitochondrial dysfunction in disease (Aug 2018)
    • Lipid mediators of disease (Jul 2018)
    • Cellular senescence in human disease (Apr 2018)
    • View all review series...
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Scientific Show Stoppers
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • About
  • Editors
  • Consulting Editors
  • For authors
  • Current issue
  • Past issues
  • By specialty
  • Subscribe
  • Alerts
  • Advertise
  • Contact
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • Brief Reports
  • Technical Advances
  • Commentaries
  • Editorials
  • Hindsight
  • Review series
  • Reviews
  • The Attending Physician
  • First Author Perspectives
  • Scientific Show Stoppers
  • Top read articles
  • Concise Communication
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 November 1, 2012; First published October 24, 2012
Citation Information: J Clin Invest. 2012;122(11):4218-4230. https://doi.org/10.1172/JCI59176.
View: Text | PDF
Category: Research Article

Hypoxic pulmonary vasoconstriction requires connexin 40–mediated endothelial signal conduction

  • Text
  • PDF
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

×

Figure 5

Cx40 deficiency attenuates chronic hypoxic pulmonary hypertension.

Options: View larger image (or click on image) Download as PowerPoint
Cx40 deficiency attenuates chronic hypoxic pulmonary hypertension.
Group...
Group data showing (A) right ventricular systolic pressure (RVSP) and (B) right ventricular weight relative to septal and left ventricular weight (Fulton index) in Cx40+/+ and Cx40–/– mice housed in either normoxia (21% O2) or hypoxia (10% O2) for 5 weeks. (C) Representative images of H&E-stained lung sections showing pulmonary arterioles (denoted by 4 arrowheads each). Scale bar: 50 μm. (D) Group data (n = 8 mice each) showing degree of vascular muscularization in pulmonary arterioles 20–50 μm in diameter, expressed as proportion of non-, partially, or fully muscularized vessels, in lungs from normoxic and hypoxic Cx40+/+ and Cx40–/– mice. *P < 0.05 vs. normoxia; #P < 0.05 vs. Cx40+/+.
Follow JCI:
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts