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.
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.
RNA sequencing study using Prox1-eGFP mice to investigate the role of lymphatic vasculature in chronic cardiac dysfunctionNCBI Gene Expression Omnibus, GSE150041.
- 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.
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)."
- Gou Young Koh, Institute of Basic Science and Korea Advanced Institute of Science and Technology (KAIST), Korea (South), Republic of
© 2020, Song et al.
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