Lymphangiogenic therapy prevents cardiac dysfunction by ameliorating inflammation and hypertension.

Loujin Song,Hanna Sobon,Teresa Cunio,Sabra D Al-Harthy,Shoh Asano,Youngwook Ahn,Steven Kreuser,Casey Ritenour,Xian Chen,Katherine Hales,Arun Shipstone,Magalie Boucher,Brianna Laviolette,Jincheng Pang,Frank Voigt,William C Sessa ,Fu-Rong Sun ,Terri A Swanson ,Michael W Nagle ,Andrew W Robertson ,Rachel J Roth Flach

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.

Highlights

The lymphatic vasculature plays an important role in mediating fluid balance and local inflammation in many tissues and organs throughout the body (Huang et al, 2017; Oliver et al, 2020)
A significant (19.6% for VEGFC, 38.8% for LYVE1 and 21.7% for FLT4 on average) reduction was observed for lymphatic markers VEGFC, LYVE1, and FLT4, and a 31.6% reduction was observed in PDPN (p=0.07) in hearts from chronic heart failure patients compared with hearts from healthy donors (Figure 1A–D, Figure 1—source data 1), suggesting that the cardiac lymphatic vasculature is impaired in human chronic heart failure
Recent studies indicated that the lymphatic vasculature, a traditionally-neglected target for therapeutic interventions, plays an important role in the pathogenesis of cardiovascular diseases, and enhancing lymphangiogenesis could be beneficial for acute cardiac injuries (Henri et al, 2016; Houssari et al, 2020; Huang et al, 2017; Klotz et al, 2015; Liu and Oliver, 2019; Shimizu et al, 2018; Tatin et al, 2017; Trincot et al, 2019; Vieira et al, 2018; Vivien et al, 2019)

Summary

Introduction

The lymphatic vasculature plays an important role in mediating fluid balance and local inflammation in many tissues and organs throughout the body (Huang et al, 2017; Oliver et al, 2020). The heart carries a complex lymphatic network and relies on cardiac lymphatics to drain interstitial fluids and immune cells for maintaining homeostasis (Brakenhielm and Alitalo, 2019). Disrupting cardiac lymphatics can cause myocardial edema and lead to impaired cardiac function (Cui et al, 2001; Mehlhorn et al, 1995), indicating a critical role of cardiac lymphatics in cardiovascular physiology. Cardiac lymphatics have emerged as a new therapeutic target for acute cardiac injuries. Several studies have demonstrated using rodent models that therapeutic lymphangiogenesis

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