Age-associated loss of lymphatic vessels promotes cardiac inflammation

Aging is a major risk factor for cardiovascular disease, but the role of the cardiac lymphatic vasculature in this process remains poorly understood. Here we show that aging reduces cardiac lymphatic vessel density in humans and mice and induces structural remodeling characterized by tighter, zipper-like endothelial junctions. These changes are associated with immune cell infiltration, fibrinogen and amyloid accumulation, and myocardial edema. Selective reduction of cardiac lymphatics in young mice, through Flt4 (VEGFR3) depletion or soluble Flt4 overexpression, recapitulates key features of cardiac aging, including inflammation and impaired lymphatic integrity. Mechanistically, aging induces selective upregulation of nuclear interleukin-33 (IL-33) in lymphatic endothelial cells. Unlike extracellular IL-33, nuclear IL-33 promotes lymphatic endothelial cell death and junctional remodeling. We identify VEGFC as an age-sensitive regulator that declines with aging and suppresses IL-33. Cardiac Vegfc overexpression or Il33 silencing restores lymphatic density and tissue homeostasis in aged hearts, identifying a potential therapeutic target for age-related cardiac dysfunction.

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Publication Details

Journal
Nature Cardiovascular Research
Published
2026-09-15
DOI
https://doi.org/10.1038/s44161-026-00870-y
Citations
1
Primary Topic
Lymphatic System and Diseases
Type
article
Field-Weighted Citation Impact
3.75

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article

Age-associated loss of lymphatic vessels promotes cardiac inflammation

Emmanouil G Solomonidis, Manfred Ogris, David John, Susanne Hille et al.
1 citations
Nature Cardiovascular Research
Lymphatic System and Diseases
3.75
article

Age-associated loss of lymphatic vessels promotes cardiac inflammation

Emmanouil G Solomonidis, Manfred Ogris, David John, Susanne Hille, Simone-Franziska Glaser, Jochen Pöling, Marek Bartkuhn, Kari Alitalo, Stefanie Dimmeler, Salli Antila, Evelyn Ullrich, Thomas Braun, Laia Cañes, Julian U. G. Wagner, Christian Kupatt, Oliver J. Müller, David Rodríguez Morales, Mariano Ruz Jurado, Christoph Kugler, Josefine Panthel, Katja Schmitz, Haris Kujundzic, Sarmad Ahmad Khan, Ibrahim Sultan, F Buettner, Tarik Bozoglu, Haider Sami, Wesley T. Abplanalp, Marion Muhly-Reinholz, Hamza Gulshan, Tara Procida-Kowalski
article en
1 citations

Abstract

Aging is a major risk factor for cardiovascular disease, but the role of the cardiac lymphatic vasculature in this process remains poorly understood. Here we show that aging reduces cardiac lymphatic vessel density in humans and mice and induces structural remodeling characterized by tighter, zipper-like endothelial junctions. These changes are associated with immune cell infiltration, fibrinogen and amyloid accumulation, and myocardial edema. Selective reduction of cardiac lymphatics in young mice, through Flt4 (VEGFR3) depletion or soluble Flt4 overexpression, recapitulates key features of cardiac aging, including inflammation and impaired lymphatic integrity. Mechanistically, aging induces selective upregulation of nuclear interleukin-33 (IL-33) in lymphatic endothelial cells. Unlike extracellular IL-33, nuclear IL-33 promotes lymphatic endothelial cell death and junctional remodeling. We identify VEGFC as an age-sensitive regulator that declines with aging and suppresses IL-33. Cardiac Vegfc overexpression or Il33 silencing restores lymphatic density and tissue homeostasis in aged hearts, identifying a potential therapeutic target for age-related cardiac dysfunction.

Nature Cardiovascular Research
Goethe University Frankfurt (DE), University of Vienna (AT), University of Helsinki (FI), German Cancer Research Center (DE), Justus-Liebig-Universität Gießen (DE), Frankfurt Institute for Advanced Studies (DE), TUM Klinikum (DE), Wihuri Research Institute (FI), Max Planck Institute for Heart and Lung Research (DE), German Cancer Society (DE), Schüchtermann-Klinik (DE), University Hospital Schleswig-Holstein (DE), German Centre for Cardiovascular Research (DE), University Hospital Frankfurt (DE), Cardio-Pulmonary Institute (DE), Frankfurt Cancer Institute (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), Technical University of Munich (DE), University of Lübeck (DE)
European Molecular Biology Organization, Helsingin Yliopisto, Deutsches Krebsforschungszentrum, Deutsches Zentrum für Herz-Kreislaufforschung, European Commission, Deutsche Forschungsgemeinschaft, Universität Wien, Novo Nordisk, Goethe-Universität Frankfurt am Main, Technische Universität München, Deutsche Krebshilfe, Sigrid Juséliuksen Säätiö, Novo Nordisk Fonden, Deutschen Konsortium für Translationale Krebsforschung, Cardio-Pulmonary Institute
Good health and well-being
Openalex Percentile: Top 5%
Lymphatic System and Diseases
3.75
DOIOpen Access PDFOpenAlex
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