A joint team led by Professor Ho Min Kim of the Department of Biological Sciences at the Korea Advanced Institute of Science and Technology (KAIST) and Dr. Sangkyu Lee of the Institute for Basic Science (IBS) has determined the three-dimensional structure of the VEGF-C–VEGFR-3 complex, the central molecular interaction that triggers lymphangiogenesis, the formation of lymphatic vessels. In doing so, the team identified an unexpected layer of regulation: after the initial binding event, multiple receptor complexes gather side by side along the cell membrane, forming higher-order clusters that dramatically amplify the signal transmitted into the cell. The findings were published online on September 9 in the international journal Advanced Science under the title “Structural Basis of Lymphangiogenic Receptor VEGFR-3 Activation Mediated by Distinctive Clustering of the Ligand–Receptor Complex.”

To understand the significance of the discovery, it helps to consider how lymphangiogenic signaling has traditionally been viewed. Vascular endothelial growth factor C, or VEGF-C, is a protein that circulates through the extracellular environment and binds to VEGFR-3, a receptor embedded in the membrane of lymphatic endothelial cells. When VEGF-C engages VEGFR-3, two receptor molecules are brought together in a dimer, and this dimerization has long been considered the decisive step that switches the receptor on. Once activated, VEGFR-3 initiates intracellular signaling cascades, including the ERK pathway, that instruct the cell to proliferate, migrate, and organize into new lymphatic vessels. What happened after dimerization, however, and how the signal might be boosted beyond that initial pairing, remained poorly understood.

The KAIST and IBS researchers turned to cryogenic electron microscopy, or cryo-EM, a technique that flash-freezes protein samples at extremely low temperatures and images them with electron beams to reveal molecular structures at near-atomic resolution. Using this approach, the team visualized the VEGF-C–VEGFR-3 complex in unprecedented detail and made a striking observation: the complexes did not remain as isolated pairs. Instead, multiple VEGF-C–VEGFR-3 assemblies lined up alongside one another in the plane of the cell membrane, forming two distinct types of higher-order clusters. Cryo-EM observation showed that these assemblies organize laterally, creating an architecture that had never been described for this receptor system before.

Among the clustered arrangements, the researchers succeeded in determining the three-dimensional structure of what they term the cis-cluster, a configuration in which multiple VEGF-C–VEGFR-3 complexes are aligned side by side. The analogy the researchers draw is straightforward: two people first form a team to begin a task, and then multiple teams gather together to increase their collective strength. In molecular terms, the ligand-induced dimer represents the formation of the individual team, while the cis-cluster represents the assembly of teams into a larger, more powerful collective unit capable of generating a stronger signal inside the cell.

Crucially, the team did not stop at structural observation. They designed experiments to test whether this clustering actually matters for signaling output. By mutating VEGFR-3 at the regions where the complexes contact one another, they disrupted the ability of the complexes to form cis-clusters. The result was unambiguous: even when VEGF-C was present and able to bind the receptor, the activation of VEGFR-3 and of the downstream ERK signaling molecule was markedly reduced. The researchers also used light-based approaches to control receptor clustering directly, further confirming that the gathering of multiple complexes plays an essential role in amplifying the lymphangiogenic signal.

This identification of clustering as an amplification mechanism effectively reveals a new control point in the signaling pathway, one that Professor Kim has described as a previously unseen “hidden amplification switch” in lymphangiogenic signaling. According to Kim, the study reveals how two VEGFR-3 receptors first form a ligand-induced pair, after which multiple such complexes cluster together to further amplify the signal for lymphangiogenesis. He added that the work is expected to provide an important foundation for developing new therapeutic strategies for related diseases such as lymphedema and cancer metastasis.

The therapeutic logic cuts in two directions. In diseases such as lymphedema, where lymphatic vessel formation is insufficient, a drug that enhances VEGF-C–VEGFR-3 clustering could potentially strengthen the growth signals and encourage the regeneration of functional drainage vessels. Conversely, in cancer, where excessive lymphatic vessel growth around a tumor creates routes for metastatic spread, a molecule that blocks the contact surfaces required for cis-cluster formation could dampen signaling and starve the tumor of its lymphatic escape routes. The same structural interface that the KAIST team mapped in cryo-EM detail thus represents a potential target for both promoting and suppressing lymphangiogenesis, depending on the clinical context.

The researchers are careful to note the limits of the current work. The study did not demonstrate therapeutic effects for lymphedema or the inhibition of cancer metastasis, and considerable further research will be required before the findings can be translated into actual treatments. Structural biology of this kind provides the blueprint rather than the drug: knowing precisely how the complexes contact one another gives medicinal chemists and biologists a concrete molecular target, but designing molecules that safely modulate that interface in patients remains a long road involving drug discovery, preclinical testing, and clinical trials.

The work was a collaborative effort involving multiple contributors. Dr. Ryeongeun Cho of the KAIST InnoCORE AI-CRED Innovative Drug Research Group and Dr. Jinsook Ahn of the KAIST Department of Biological Sciences participated as co-first authors, while Professor Ho Min Kim and Dr. Sangkyu Lee served as co-corresponding authors. The research was supported by the National Research Foundation of Korea, the InnoCORE program of the Ministry of Science and ICT, the NEXUS and CELINE consortium, the KAIST Convergence Research Institute Operation Program, and the Institute for Basic Science, among others. As the structural details of the VEGF-C–VEGFR-3 cis-cluster circulate through the scientific community, the discovery stands as a vivid reminder that even well-studied signaling pathways can conceal entire layers of regulation, and that the tools of modern cryo-EM are increasingly capable of bringing those hidden mechanisms into focus.

Subject of Research: Structural basis of VEGF-C–VEGFR-3 receptor clustering in lymphangiogenic signaling

Article Title: KAIST identifies a “hidden amplification switch” in lymphangiogenic signaling, with implications for lymphedema and cancer metastasis

Article References: KAIST identifies a “hidden amplification switch” in lymphangiogenic signaling, with implications for lymphedema and cancer metastasis. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: VEGF-C, VEGFR-3, lymphangiogenesis, cryo-EM, lymphedema, cancer metastasis, receptor clustering, signal amplification, KAIST, Institute for Basic Science, Advanced Science, structural biology

The scale of the problem the review addresses is hard to overstate. Obesity has become a global public health crisis, and according to the World Obesity Federation’s 2025 atlas its continued rise poses significant risks for cardiovascular disease, type 2 diabetes and several cancers, while reducing life expectancy. Traditional explanations have centered on energy balance, adipose tissue expansion and chronic low-grade inflammation. What has been missing, the authors contend, is a systematic account of how the lymphatic vasculature participates in this pathology. Their review, published on 25 September 2026, sets out to map the mechanisms of interaction between lymphatic dysfunction and obesity, and to ask which direction the causality runs, a question that remains only partially answered.

Understanding the argument requires appreciating how unusual lymphatic vessels are at the structural level. Unlike blood vessels, collecting lymphatics are lined by endothelial cells joined by specialized button-like junctions that act as flaps, allowing fluid, proteins and immune cells to enter freely while preventing backflow. In the intestine, these vessels form lacteals, blind-ended capillaries in each villus that absorb dietary fat packaged into chylomicrons. The junctions between lacteal endothelial cells are remarkably plastic: work cited in the review showed that zippering these junctions shut in mice protects against diet-induced obesity by limiting fat uptake, while fibroblast subsets in the villi regulate lacteal integrity through YAP/TAZ-driven production of vascular endothelial growth factor C, or VEGF-C. In other words, the architecture of the lymphatic drainage system directly tunes how many calories the gut absorbs.

The molecular machinery governing lymphatic identity and function is equally central to the story. The transcription factor Prox1 induces the lymphatic endothelial phenotype, working with COUP-TFII to specify cell fate, while the VEGF-C/VEGFR-3 signaling axis drives lymphangiogenesis, the growth of new lymphatic vessels. VEGFR-3 signaling is required for button junction formation, and ligand-induced heterodimerization with VEGFR-2 shapes phosphorylation patterns in lymphatic endothelial cells. Other players refine the network further: semaphorin 3A, neuropilin-1 and plexin-A1 are needed for lymphatic valve formation, FOXC2 and fluid shear stress stabilize vessels after birth, and eNOS controls valve specification through beta-catenin signaling. When any of these pathways falter, the consequences ripple outward, because lymphatics do far more than drain fluid. They mediate macrophage reverse cholesterol transport, remove cholesterol from peripheral tissues via SR-BI-mediated HDL transport, and serve as gatekeepers that shape immune tolerance through molecules such as PD-L1.

Against this backdrop, the evidence that obesity damages lymphatics is strikingly consistent. Mouse studies have shown that obesity impairs lymphatic fluid transport and dendritic cell migration to lymph nodes, and that chronic high-fat feeding degrades collecting vessel function even before gross metabolic disease appears. Hypercholesterolemic mice exhibit lymphatic vessel dysfunction and degeneration, and ApoE-deficient animals show multiple facets of lymphatic failure, including valve dysfunction on western diets. In obese animals, mesenteric lymph nodes display increased fibrosis and altered immune cellularity, and obesity-associated lymph leakage impairs the trafficking of lipids, lipophilic drugs and antigens from the intestine. Mechanistically, inflammatory cytokines appear to be key culprits: tumor necrosis factor alpha inhibits lymphatic pumping through the NF-kappaB and inducible nitric oxide synthase pathway, and inflammatory mediators disrupt endothelial barrier function. Obesity, in this framing, is an environment in which lymphatic vessels progressively choke.

Crucially, the review emphasizes that the damage is not merely collateral. Lymphatic insufficiency feeds back into metabolic disease. Mesenteric lymphatic dysfunction has been shown to promote insulin resistance, positioning the lymphatic system as a potential treatment target rather than a passive victim. Deletion of the fatty acid transporter CD36 specifically in lymphatic endothelial cells associates with visceral obesity and insulin resistance, while RAMP1 signaling deletion enhances diet-induced obesity and fat absorption through intestinal lacteals. In Prox1-haploinsufficient mice, which have inherently compromised lymphatics, restoring lymphatic function rescued the obese phenotype, one of the most direct demonstrations that lymphatic failure can cause obesity rather than simply accompany it. Lymphatic vessel insufficiency in hypercholesterolemic mice also alters lipoprotein levels and promotes atherosclerosis, extending the loop to cardiovascular disease.

The immune dimension adds another layer of complexity. Adipose tissue in obesity accumulates macrophages, and a paracrine loop between adipocytes and macrophages, driven by free fatty acids and tumor necrosis factor alpha, aggravates inflammation. Adipokines modulate this crosstalk: leptin, elevated in obesity, compromises lymphatic endothelial cell homeostasis by impairing tube formation and proliferation, and leptin-VEGF crosstalk has been implicated in excess body mass and related disorders. Adiponectin, by contrast, protects the system, modulating lymphatic vessel formation and reducing lymphedema. T lymphocytes negatively regulate lymph node lymphatic vessel formation, Th2 cytokines inhibit lymphangiogenesis, and transforming growth factor beta 1 blockade accelerates lymphatic regeneration during wound repair. Specialized pro-resolving mediators such as lipoxins interact with the lymphatic system to resolve inflammation, suggesting that the vessels are active participants in the inflammatory arc of obesity, from ignition to resolution.

What makes the review timely is its treatment implications. The authors highlight that obesity-induced lymphatic dysfunction is reversible with weight loss, and that exercise training improves obesity-related lymphatic dysfunction in animal models. A lymphoscintigraphic study found that lower extremity lymphatic function can be predicted by body mass index, linking clinical imaging to the mechanistic work. Inhibition of inflammation and inducible nitric oxide synthase improves lymphatic function in obesity, and a case report described semaglutide treatment in a patient with extreme obesity and massive lymphedema, hinting that the new generation of metabolic drugs may act partly through lymphatic pathways. Manual lymphatic drainage has been shown to alter adipokine and cytokine concentrations and markers of insulin resistance in patients with abnormal body mass index, while electroacupuncture combined with intradermal needling has been reported to influence serum markers of intestinal lymphatic function in simple obesity. Even GLP-2 has been shown to stimulate lacteal contractility and enhance chylomicron transport when the enteric nervous system is intact.

The therapeutic frontier the review sketches is correspondingly broad. Pharmacological modulation of the VEGF-C/VEGFR-3 axis could either promote lymphatic growth where vessels have failed or, in the intestinal context, be tuned to limit fat absorption, since blockade of VEGF-C and VEGF-D has been shown to modulate adipose tissue inflammation and improve metabolic parameters under high-fat diet conditions. Apelin, which inhibits diet-induced obesity by enhancing lymphatic and blood vessel integrity, represents another candidate pathway, as do receptors such as GPR182, recently identified as a lipoprotein receptor for dietary fat absorption, and the ERAD machinery protein AIDA, which selectively downregulates fat synthesis enzymes to retard intestinal fat uptake and prevent obesity. Targeting lymphatic muscle cells, valve function and junctional zippering each offer distinct intervention points, though the authors are careful to note that the directionality of causality between lymphatic dysfunction and obesity is not yet fully resolved, and that much of the evidence remains preclinical.

The broader significance of the work lies in reframing. If the lymphatic system sits at the junction of fat absorption, cholesterol trafficking, immune signaling and inflammation resolution, then it is not a peripheral curiosity in metabolic disease but a potential control node. The review, funded by the National Natural Science Foundation of China, systematically assembles the case that protecting or restoring lymphatic function could complement diet, exercise and incretin-based therapies, and that lymphatic biomarkers might one day identify patients at risk of obesity-driven metabolic complications before they manifest. It also raises an urgent clinical question: with obesity-linked lymphedema rising alongside waistlines worldwide, understanding the bidirectional crosstalk between fat and lymph may prove essential to treating both. The vessels that drain our tissues, long overlooked, may hold one of the keys to the obesity epidemic.

Subject of Research: Bidirectional relationship between lymphatic dysfunction and obesity in metabolic disease pathogenesis and therapy

Article Title: Bidirectional crosstalk between obesity and the lymphatic system: a novel pathway in obesity pathogenesis and treatment

Article References: Hao, Y., Zhang, Y., Zong, J., Wu, G., Wang, Y., Wang, J., & Wang, Y. (2026). Bidirectional crosstalk between obesity and the lymphatic system: a novel pathway in obesity pathogenesis and treatment. International Journal of Obesity. https://doi.org/10.1038/s41366-026-02178-0

Image Credits: AI Generated

DOI: 10.1038/s41366-026-02178-0

Keywords: obesity, lymphatic system, lymphatic dysfunction, VEGF-C, lacteals, lipid metabolism, inflammation, insulin resistance, lymphangiogenesis, adipokines, metabolic disease, lymphedema

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