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Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension

Research Article
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Cite this article as: eLife 2020;9:e58376 doi: 10.7554/eLife.58376

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.

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)

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.

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