Age-associated loss of lymphatic vessels promotes cardiac inflammation.

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

Institute for Cardiovascular Regeneration, Goethe-University Frankfurt, Frankfurt am Main, Germany. [email protected] for Cardiovascular Regeneration, Goethe-University Frankfurt, Frankfurt am Main, Germany. [email protected]. · pubmed

Paper

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.

The following analysis is generated by AI and may contain errors. It is separate from the authors’ abstract and is not peer review.

Research summary

Aging induces nuclear IL-33 upregulation in cardiac lymphatic endothelial cells, leading to lymphatic loss and inflammation, which can be reversed by VEGFC overexpression. This paper is relevant because it identifies a specific molecular mechanism (nuclear IL-33/VEGFC axis) driving a fundamental aspect of tissue aging (lymphatic degeneration) and demonstrates that restoring this pathway can reverse age-associated cardiac pathology, offering a potential intervention for age-related organ dysfunction rather than just treating downstream symptoms.

Author of this paper? Send a correction.