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
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.