Aging Lymphatic Vessels Fuel Heart Inflammation, and a Growth Factor May Reverse It

The aging heart carries more than worn muscle fibers and stiffened arteries. Beneath the familiar hallmarks of cardiac aging lies a quieter, less celebrated network: the lymphatic vessels, which drain fluid, shuttle immune cells, and keep inflammation in check. A new study published in Nature Cardiovascular Research now shows that the gradual deterioration of this network with age is not a bystander but an active driver of cardiac inflammation, and that the process may be counteracted by boosting a single vascular growth factor in the heart.

The research, led by Wagner and colleagues, centers on lymphatic endothelial cells, the specialized cells that line the interior of lymphatic vessels. In the heart, these vessels perform a demanding job. They clear interstitial fluid and macromolecules that accumulate as blood plasma filters out of coronary capillaries, and they provide the principal routes by which antigen-bearing immune cells migrate away from cardiac tissue and toward the draining lymph nodes. When lymphatic drainage falters, fluid and immune mediators build up in the tissue, and the heart’s immune environment shifts from a controlled, surveilled state to a chronically inflamed one.

By comparing lymphatic vessels in young and aged hearts, the investigators found that lymphatic integrity declines markedly with age. Lymphatic endothelial cells in older hearts showed structural and functional impairment, and the lymphatic network itself lost density and organization. This age-associated loss of lymphatic vasculature was consistently accompanied by heightened cardiac inflammation, including accumulation of inflammatory immune cells within heart tissue. The correlation raised a critical mechanistic question: is the lymphatic decline merely a consequence of inflammation, or does it actively promote the inflammatory state of the aging heart?

The study’s central finding points to the lymphatic defect as a cause rather than a consequence. The authors traced the impairment to elevated levels of nuclear interleukin-33, an immune regulatory protein, within the lymphatic endothelial cells themselves. Interleukin-33 is a member of the interleukin-1 cytokine family and is typically regarded as an alarmin, a danger signal released by stressed or damaged cells. Its cellular distribution matters enormously: when resident in the nucleus, it can regulate gene expression programs, while extracellular interleukin-33 acts as a potent immune activator through its receptor ST2. The new work indicates that in aged lymphatic endothelial cells, increased nuclear interleukin-33 expression disrupts the cells’ homeostatic function and undermines the structural integrity of the lymphatic network they support.

This mechanistic identification is what elevates the study from descriptive observation to a testable model of cardiac aging. Interleukin-33 signaling has long been implicated in inflammatory and fibrotic processes across multiple tissues, but its role within cardiac lymphatic endothelial cells had remained poorly defined. By localizing the pathological signal to the nucleus of the cells responsible for lymphatic vessel maintenance, the researchers uncovered a cell-autonomous mechanism by which the heart’s own drainage system degrades with age. The result is a self-reinforcing cycle: compromised lymphatic clearance permits inflammatory mediators to persist in the tissue, and the resulting inflammatory milieu further stresses the lymphatic endothelium, deepening the dysfunction.

Crucially, the researchers did not stop at describing the failure. They tested whether the decline could be reversed. Using cardiac overexpression of vascular endothelial growth factor C, or Vegfc, the master growth factor governing lymphatic vessel development and maintenance, they were able to counteract the age-related lymphatic deterioration. Vegfc signals through its receptor VEGFR-3 on lymphatic endothelial cells, promoting their survival, proliferation, and sprouting, and it is the pivotal driver of lymphangiogenesis, the formation of new lymphatic vessels. When Vegfc was overexpressed in the aging heart, the integrity of the lymphatic network improved, suggesting that the age-associated loss of lymphatic vasculature is not an irreversible consequence of time but a dynamic, modifiable process.

The therapeutic implications are substantial. Current approaches to cardiac aging and inflammation largely target the inflammatory cells themselves or downstream cytokines, strategies that often carry broad immunosuppressive consequences. Restoring the heart’s lymphatic drainage offers a fundamentally different intervention point. Rather than dampening the immune response indiscriminately, lymphatic-targeted therapy would strengthen the structural system that normally regulates immune cell traffic and fluid balance, potentially resolving inflammation by addressing one of its upstream causes. The finding that Vegfc overexpression can rescue aged lymphatic vessels provides a proof of principle that this axis is pharmacologically accessible.

The study also reframes how the field understands interstitial physiology in the aging heart. The myocardial interstitium, the space between heart muscle cells and capillaries, is not an inert filler but a dynamically regulated compartment. Its composition depends on a continuous balance of fluid filtration from the blood, drainage through the lymphatic system, and clearance of extracellular matrix components and metabolic byproducts. Age-related lymphatic impairment tips this balance toward accumulation, creating a microenvironment that favors fibroblast activation, matrix deposition, and chronic immune cell infiltration, all recognized contributors to cardiac fibrosis and declining heart function in the elderly.

Questions remain before these findings can be translated into clinical strategies. The precise transcriptional programs by which nuclear interleukin-33 disrupts lymphatic endothelial cell function have not been fully delineated, and it is not yet clear whether pharmacological modulation of interleukin-33 itself, rather than Vegfc-based promotion of lymphatic growth, could also interrupt the pathological cycle. The long-term safety of stimulating lymphatic growth in the heart, particularly in the context of other cardiovascular diseases such as ischemic heart disease or heart failure, will require dedicated investigation. Dosing, timing, and the reversibility of lymphatic injury at different stages of aging are all open territory. Nonetheless, the identification of a defined molecular driver and a corresponding molecular rescue establishes a clear experimental roadmap.

For a rapidly aging global population, in which heart disease remains the leading cause of death, interventions that address the underlying biology of cardiac aging carry enormous public health weight. The demonstration that a vascular system long treated as peripheral to cardiovascular medicine plays a causative role in age-related cardiac inflammation adds lymphatic vessel maintenance to the growing list of tissues and pathways implicated in healthy aging. If the Vegfc–interleukin-33 axis can be safely harnessed in humans, the heart’s own drainage network may one day become a target for keeping the aging myocardium calm, well-drained, and resilient.

Subject of Research: Age-associated loss of cardiac lymphatic vessels driven by nuclear interleukin-33 in lymphatic endothelial cells and its reversal by Vegfc overexpression

Article Title: Age-associated loss of lymphatic vessels promotes cardiac inflammation

Article References: Wagner, J. U. G., Gulshan, H., Sultan, I., Antila, S., Esteve, L.-C., Rodriguez Morales, D., Ruz Jurado, M., John, D., Solomonidis, E. G., Schmitz, K., Panthel, J., Kujundzic, H., Hille, S., Müller, O. J., Kugler, C., Sami, H., Ogris, M., Glaser, S.-F., Abplanalp, W. T., … Dimmeler, S. (2026). Age-associated loss of lymphatic vessels promotes cardiac inflammation. Nature Cardiovascular Research. https://doi.org/10.1038/s44161-026-00870-y

Image Credits: AI Generated

DOI: 10.1038/s44161-026-00870-y

Keywords: cardiac lymphatic vessels, aging, lymphatic endothelial cells, interleukin-33, VEGFC, cardiac inflammation, lymphangiogenesis, heart aging, VEGFR-3, cardiac fibrosis, immune cell trafficking, Nature Cardiovascular Research