Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension
- Pfizer Inc, United States
- Acceleron Pharma, United States
- Eisai Inc, United States
- Yale School of Medicine, United States
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.
Article and author information
Author details
Rachel J Roth Flach
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.
Reviewing Editor
- Gou Young Koh, Institute of Basic Science and Korea Advanced Institute of Science and Technology (KAIST), Korea (South), Republic of
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)."
Version history
- Received: April 29, 2020
- Accepted: November 16, 2020
- Accepted Manuscript published: November 17, 2020 (version 1)
- 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.
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Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension
eLife 9:e58376.
https://doi.org/10.7554/eLife.58376
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