Skip to main content

Main menu

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • ERS Guidelines
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • Peer reviewer login
  • Alerts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • ERS Guidelines
  • Authors/reviewers
    • Instructions for authors
    • Submit a manuscript
    • Open access
    • Peer reviewer login
  • Alerts
  • Subscriptions

Connecting the dots: the role of connexins in the pulmonary vascular response to hypoxia

Martin Witzenrath, Wolfgang M. Kuebler
European Respiratory Journal 2021 57: 2004573; DOI: 10.1183/13993003.04573-2020
Martin Witzenrath
1Dept of Infectious Diseases and Respiratory Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wolfgang M. Kuebler
2Institute of Physiology, Charité – Universitätsmedizin Berlin, Berlin, Germany
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: Wolfgang.Kuebler@charite.de
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Gap junctions, composed of connexins 37, 40 or 43, mediate the pulmonary vascular response to acute and chronic hypoxia as they propagate the hypoxic signal from the site of gas exchange retrogradely to the feeding arteri(ol)es https://bit.ly/3orJKXM

To the Editor:

We read with great interest the recent manuscript by Bouvard et al. [1], which suggested the gap junctional protein connexin-43 (Cx43) to be a promising target for the treatment of chronic hypoxic pulmonary hypertension (CHPH). Therein, the authors demonstrated increased Cx43 expression in human pulmonary arteries of CHPH patients, while heterozygous Cx43 deficient mice were partially protected from CHPH.

These findings align with a series of previous studies highlighting the role of connexins in the pulmonary vascular response to hypoxia: I. McMurtry and co-workers first reported that the non-specific gap junction blocker 18α-glycyrrhetinic acid blunts the acute vasoconstrictive response to hypoxia in isolated perfused rat lungs [2]. Using a combination of small peptide inhibitors and gene deficient mice, subsequent work by our own groups demonstrated that both connexin-40 (Cx40) and Cx43 contribute additively to hypoxic pulmonary vasoconstriction, and that Cx40 deficient mice are largely protected from the development of CHPH [3]. Attenuation of the vasoconstrictive response of pulmonary arteries to hypoxia in vivo and ex vivo by 18α-glycyrrhetinic acid was further confirmed by the laboratory of J.P.T. Ward and P.I. Aaronson [4]. Consistent with these reports, the findings by Bouvard et al. [1] consolidate the requirement of connexins for the pulmonary vascular response to hypoxia. Notably, however, this concept has recently been challenged by a report that Cx40 deficient mice develop more severe CHPH, which can be attenuated by adenoviral Cx40 overexpression [5]. The reason for the obvious discrepancy between these [5] and earlier [3] findings remains unclear.

Connexins are the building blocks of gap junctions, i.e. they form intercellular communication “channels” composed of two opposing homo- or heterotypic (i.e. identical or not) connexons, each of which is again a hexamer consisting of six identical (homomeric) or different (heteromeric) connexins [6]. In the vasculature, gap junctions are typically composed of one of three connexins, namely connexins 37, 40 and 43 [6]. In the systemic circulation, vascular gap junctions have been long recognised as important “highways” for retrograde signal conduction from capillaries to upstream arterioles in order to match resistance vessel tone and, thus, blood flow to local demands in the “downstream” tissue. In the lung, an analogous signal propagation from capillaries to upstream arterioles mediates the pulmonary vascular response to hypoxia. This signal conduction is required due to the spatial separation between the site of gas exchange, i.e. the alveolo-capillary compartment, and the site of vasoconstriction and vascular remodelling in response to acute and chronic hypoxia, respectively, which are localised in upstream arterioles [3, 7]. Although direct visualisation of gas exchange in intact lungs by multispectral oximetry has revealed relevant precapillary oxygenation, indicating that alveolar hypoxia can directly impact oxygen tension (PO2) in the vascular wall of precapillary pulmonary vessels, this phenomenon is restricted to arterioles of <30 µm in diameter [8]. PO2 in the vascular wall of larger vessels is, conversely, determined by central venous PO2, which is, however, not an adequate trigger for hypoxic vasoconstriction and remodelling in the lung [9]. Hence, vasoconstriction and remodelling of pulmonary arteries >30 mm in response to acute or chronic hypoxia requires retrograde signal propagation along the vascular wall. Gap junctions facilitate such intercellular communication by propagating changes in cell membrane potential along either the endothelial or the smooth muscle layer, or between the two cell types via so-called myo-endothelial gap junctions. In line with the concept of such a conducted response, direct imaging of endothelial membrane potential in intact lungs revealed endothelial depolarisation in alveolar capillaries in response to hypoxia that propagated upstream to feeding arterioles in wild type, but not in Cx40-deficient mice [3].

While the expression of Cx40 in pulmonary vessels is restricted to the arteriolar and capillary endothelium, Cx43 is expressed in both endothelial and smooth muscle cells and may as such propagate changes in membrane potential along the intimal or medial layer, or between both. Notably, combined application of inhibitory mimetic peptides for both Cx40 and Cx43 causes an additive inhibitory effect on hypoxic pulmonary vasoconstriction as compared to each inhibitory peptide alone, indicating that different connexins serve distinct roles in the propagation of hypoxia. Consistent with this concept, even the vasoconstrictive response to hypoxia in isolated pulmonary arterioles, which are exposed in toto to hypoxia and, hence, do not require retrograde signal propagation, has been found to require gap junctional communication, suggesting an important role for myo-endothelial gap junctions in the pulmonary vascular response to hypoxia [4]. Yet, whether Cx43-composed gap junctions form the structural correlate for this functional observation remains to be determined.

In addition to the need for a better understanding of the exact cell type(s) connected by Cx43-mediated signalling in the pulmonary vascular response to hypoxia, future studies may also aim to elucidate hypoxia-dependent post-translational modifications in Cx43, as Cx43-mediated gap junctional intercellular communication is critically regulated via phosphorylation of several serine residues in its carboxyl-terminus [10].

Shareable PDF

Supplementary Material

This one-page PDF can be shared freely online.

Shareable PDF ERJ-04573-2020.Shareable

Footnotes

  • Conflict of interest: M. Witzenrath has nothing to disclose.

  • Conflict of interest: W.M. Kuebler has nothing to disclose.

  • Received December 19, 2020.
  • Accepted January 20, 2021.
  • ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
https://www.ersjournals.com/user-licence

References

  1. ↵
    1. Bouvard C,
    2. Genet N,
    3. Phan C, et al.
    Connexin-43 is a promising target for pulmonary hypertension due to hypoxaemic lung disease. Eur Respir J 2020; 55: 1900169. doi:10.1183/13993003.00169-2019
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Morio Y,
    2. Carter EP,
    3. Oka M, et al.
    EDHF-mediated vasodilation involves different mechanisms in normotensive and hypertensive rat lungs. Am J Physiol Heart Circ Physiol 2003; 284: H1762–H1770. doi:10.1152/ajpheart.00831.2002
    OpenUrlCrossRefPubMedWeb of Science
  3. ↵
    1. Wang L,
    2. Yin J,
    3. Nickles HT, et al.
    Hypoxic pulmonary vasoconstriction requires connexin 40-mediated endothelial signal conduction. J Clin Invest 2012; 122: 4218–4230. doi:10.1172/JCI59176
    OpenUrlCrossRefPubMedWeb of Science
  4. ↵
    1. Kizub IV,
    2. Strielkov IV,
    3. Shaifta Y, et al.
    Gap junctions support the sustained phase of hypoxic pulmonary vasoconstriction by facilitating calcium sensitization. Cardiovasc Res 2013; 99: 404–411. doi:10.1093/cvr/cvt129
    OpenUrlCrossRefPubMed
  5. ↵
    1. Si R,
    2. Zhang Q,
    3. Cabrera JTO, et al.
    Chronic hypoxia decreases endothelial connexin 40, attenuates endothelium-dependent hyperpolarization-mediated relaxation in small distal pulmonary arteries, and leads to pulmonary hypertension. J Am Heart Assoc 2020; 9: e018327.
    OpenUrl
  6. ↵
    1. Bhattacharya J,
    2. Koval M,
    3. Kuebler WM
    . The Pulmonary Circulation. In: Tuma RF, Duran WF, Ley K, eds. The American Handbook of Physiology. Microcirculation. 2nd Edn. San Diego/Burlington/London/Amsterdam, Academic Press, 2008; pp. 712–734.
  7. ↵
    1. Grimmer B,
    2. Kuebler WM
    . The endothelium in hypoxic pulmonary vasoconstriction. J Appl Physiol (1985) 2017; 123: 1635–1646. doi:10.1152/japplphysiol.00120.2017
    OpenUrl
  8. ↵
    1. Tabuchi A,
    2. Styp-Rekowska B,
    3. Slutsky AS, et al.
    Precapillary oxygenation contributes relevantly to gas exchange in the intact lung. Am J Respir Crit Care Med 2013; 188: 474–481. doi:10.1164/rccm.201212-2177OC
    OpenUrlCrossRef
  9. ↵
    1. Dawson CA
    . Role of pulmonary vasomotion in physiology of the lung. Physiol Rev 1984; 64: 544–616. doi:10.1152/physrev.1984.64.2.544
    OpenUrlPubMedWeb of Science
  10. ↵
    1. Yogo K,
    2. Ogawa T,
    3. Akiyama M, et al.
    Identification and functional analysis of novel phosphorylation sites in Cx43 in rat primary granulosa cells. FEBS Lett 2002; 531: 132–136. doi:10.1016/S0014-5793(02)03441-5
    OpenUrlCrossRefPubMedWeb of Science
PreviousNext
Back to top
View this article with LENS
Vol 57 Issue 3 Table of Contents
European Respiratory Journal: 57 (3)
  • Table of Contents
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Connecting the dots: the role of connexins in the pulmonary vascular response to hypoxia
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Citation Tools
Connecting the dots: the role of connexins in the pulmonary vascular response to hypoxia
Martin Witzenrath, Wolfgang M. Kuebler
European Respiratory Journal Mar 2021, 57 (3) 2004573; DOI: 10.1183/13993003.04573-2020

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Connecting the dots: the role of connexins in the pulmonary vascular response to hypoxia
Martin Witzenrath, Wolfgang M. Kuebler
European Respiratory Journal Mar 2021, 57 (3) 2004573; DOI: 10.1183/13993003.04573-2020
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Abstract
    • Shareable PDF
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

Agora

  • Airway immune responses to COVID-19 vaccination in COPD patients
  • Wider access to rifapentine-based regimens is needed for TB care globally
  • Screening for PVOD in heterozygous EIF2AK4 variant carriers
Show more Agora

Correspondence

  • Treatable traits in ILD: why not consider acute exacerbations?
  • Inclusion of lung health outcomes in TB treatment trials
  • Understanding confounding in Mendelian randomisation studies
Show more Correspondence

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About the ERJ

  • Journal information
  • Editorial board
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Publication ethics and malpractice
  • Submit a manuscript

For readers

  • Alerts
  • Subjects
  • Podcasts
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Print ISSN:  0903-1936
Online ISSN: 1399-3003

Copyright © 2023 by the European Respiratory Society