Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension

Abstract

The lymphatic vasculature is involved in the pathogenesis of acute cardiac injuries, but little is known about its role in chronic cardiac dysfunction. Here, we demonstrate that angiotensin II infusion induced cardiac inflammation and fibrosis at 1 week and caused cardiac dysfunction and impaired lymphatic transport at 6 weeks in mice, while co-administration of VEGFCc156s improved these parameters. To identify novel mechanisms underlying this protection, RNA sequencing analysis in distinct cell populations revealed that VEGFCc156s specifically modulated angiotensin II-induced inflammatory responses in cardiac and peripheral lymphatic endothelial cells. Furthermore, telemetry studies showed that while angiotensin II increased blood pressure acutely in all animals, VEGFCc156s-treated animals displayed a delayed systemic reduction in blood pressure independent of alterations in angiotensin II-mediated aortic stiffness. Overall, these results demonstrate that VEGFCc156s had a multifaceted therapeutic effect to prevent angiotensin II-induced cardiac dysfunction by improving cardiac lymphatic function, alleviating fibrosis and inflammation, and ameliorating hypertension.

Data availability

RNA-Seq data has been deposited in GEO under accession code GSE150041. All other data generated during the study are included in the manuscript and supporting files. Source data has been provided for Figure 1-7.

The following data sets were generated

Article and author information

Author details

  1. LouJin Song

    Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States
    Competing interests
    LouJin Song, is an employee at Pfizer inc.
  2. Xian Chen

    Comparative Medicine, Pfizer Inc, Cambridge, United States
    Competing interests
    Xian Chen, is an employee at Pfizer inc.
  3. Terri A Swanson

    Early Clinical Development, Pfizer Inc, Cambridge, United States
    Competing interests
    Terri A Swanson, is an employee at Pfizer inc.
  4. Brianna LaViolette

    Comparative Medicine, Pfizer Inc, Cambridge, United States
    Competing interests
    Brianna LaViolette, is an employee at Pfizer inc.
  5. Jincheng Pang

    Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States
    Competing interests
    Jincheng Pang, is an employee at Pfizer inc.
  6. Teresa Cunio

    Acceleron Pharma, Cambridge, United States
    Competing interests
    Teresa Cunio, was an employee at Pfizer inc and is currently an employee at Acceleron Pharma.
  7. Michael W Nagle

    Eisai Inc, Cambridge, United States
    Competing interests
    Michael W Nagle, was an employee at Pfizer Inc. and is currently an employee at Eisai Inc.
  8. Shoh Asano

    Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States
    Competing interests
    Shoh Asano, is an employee at Pfizer Inc.
  9. Katherine Hales

    Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States
    Competing interests
    Katherine Hales, is an employee at Pfizer Inc.
  10. Arun Shipstone

    Inflammation and Immunology, Pfizer Inc, Cambridge, United States
    Competing interests
    Arun Shipstone, is an employee at Pfizer Inc.
  11. Hanna Sobon

    Inflammation and Immunology, Pfizer Inc, Cambridge, United States
    Competing interests
    Hanna Sobon, is an employee at Pfizer Inc.
  12. Sabra D Al-Harthy

    Comparative Medicine, Pfizer Inc, Cambridge, United States
    Competing interests
    Sabra D Al-Harthy, is an employee at Pfizer Inc.
  13. Youngwook Ahn

    Emerging Science and Innovation, Pfizer Inc, Cambridge, United States
    Competing interests
    Youngwook Ahn, is an employee at Pfizer Inc.
  14. Steven Kreuser

    Comparative Medicine, Pfizer Inc, Cambridge, United States
    Competing interests
    Steven Kreuser, is an employee at Pfizer Inc.
  15. Andrew Robertson

    Drug Safety Research & Development, Pfizer Inc, Cambridge, United States
    Competing interests
    Andrew Robertson, is an employee at Pfizer Inc.
  16. Casey Ritenour

    Drug Safety Research & Development, Pfizer Inc, Cambridge, United States
    Competing interests
    Casey Ritenour, is an employee at Pfizer Inc.
  17. Frank Voigt

    Drug Safety Research & Development, Pfizer Inc, Cambridge, United States
    Competing interests
    Frank Voigt, is an employee at Pfizer Inc.
  18. Magalie Boucher

    Drug Safety Research & Development, Pfizer Inc, Cambridge, United States
    Competing interests
    Magalie Boucher, is an employee at Pfizer Inc.
  19. Furong Sun

    Early Clinical Development, Pfizer Inc, Cambridge, United States
    Competing interests
    Furong Sun, is an employee at Pfizer Inc.
  20. William C Sessa

    Pharmacology, Yale School of Medicine, New Haven, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5759-1938
  21. Rachel J Roth Flach

    Internal Medicine Research Unit, Pfizer Inc, Cambridge, United States
    For correspondence
    Rachel.RothFlach@pfizer.com
    Competing interests
    Rachel J Roth Flach, is an employee at Pfizer Inc.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2754-828X

Funding

Pfizer

  • Rachel J Roth Flach

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The ethics statement has been included in the method section of the manuscript as the following:"All animal experimental procedures were carried out in accordance with regulations and established guidelines and were reviewed and approved by the Pfizer Institutional Animal Care and Use Committee(AUP # KSQ-2013-00895)."

Reviewing Editor

  1. Gou Young Koh, Institute of Basic Science and Korea Advanced Institute of Science and Technology (KAIST), Korea (South), Republic of

Publication history

  1. Received: April 29, 2020
  2. Accepted: November 16, 2020
  3. Accepted Manuscript published: November 17, 2020 (version 1)
  4. Version of Record published: November 27, 2020 (version 2)

Copyright

© 2020, Song et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,591
    Page views
  • 205
    Downloads
  • 11
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. LouJin Song
  2. Xian Chen
  3. Terri A Swanson
  4. Brianna LaViolette
  5. Jincheng Pang
  6. Teresa Cunio
  7. Michael W Nagle
  8. Shoh Asano
  9. Katherine Hales
  10. Arun Shipstone
  11. Hanna Sobon
  12. Sabra D Al-Harthy
  13. Youngwook Ahn
  14. Steven Kreuser
  15. Andrew Robertson
  16. Casey Ritenour
  17. Frank Voigt
  18. Magalie Boucher
  19. Furong Sun
  20. William C Sessa
  21. Rachel J Roth Flach
(2020)
Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension
eLife 9:e58376.
https://doi.org/10.7554/eLife.58376

Further reading

    1. Cell Biology
    Tai-De Li et al.
    Research Article

    Branched actin networks are self-assembling molecular motors that move biological membranes and drive many important cellular processes, including phagocytosis, endocytosis, and pseudopod protrusion. When confronted with opposing forces, the growth rate of these networks slows and their density increases, but the stoichiometry of key components does not change. The molecular mechanisms governing this force response are not well understood, so we used single-molecule imaging and AFM cantilever deflection to measure how applied forces affect each step in branched actin network assembly. Although load forces are observed to increase the density of growing filaments, we find that they actually decrease the rate of filament nucleation due to inhibitory interactions between actin filament ends and nucleation promoting factors. The force-induced increase in network density turns out to result from an exponential drop in the rate constant that governs filament capping. The force dependence of filament capping matches that of filament elongation and can be explained by expanding Brownian Ratchet theory to cover both processes. We tested a key prediction of this expanded theory by measuring the force-dependent activity of engineered capping protein variants and found that increasing the size of the capping protein increases its sensitivity to applied forces. In summary, we find that Brownian Ratchets underlie not only the ability of growing actin filaments to generate force but also the ability of branched actin networks to adapt their architecture to changing loads.

    1. Cell Biology
    2. Immunology and Inflammation
    Ekaterini Maria Lyras et al.
    Research Article

    The tongue is a unique muscular organ situated in the oral cavity where it is involved in taste sensation, mastication, and articulation. As a barrier organ, which is constantly exposed to environmental pathogens, the tongue is expected to host an immune cell network ensuring local immune defence. However, the composition and the transcriptional landscape of the tongue immune system are currently not completely defined. Here, we characterised the tissue-resident immune compartment of the murine tongue during development, health and disease, combining single-cell RNA-sequencing with in situ immunophenotyping. We identified distinct local immune cell populations and described two specific subsets of tongue-resident macrophages occupying discrete anatomical niches. Cx3cr1+ macrophages were located specifically in the highly innervated lamina propria beneath the tongue epidermis and at times in close proximity to fungiform papillae. Folr2+ macrophages were detected in deeper muscular tissue. In silico analysis indicated that the two macrophage subsets originate from a common proliferative precursor during early postnatal development and responded differently to systemic LPS in vivo. Our description of the under-investigated tongue immune system sets a starting point to facilitate research on tongue immune-physiology and pathology including cancer and taste disorders.