Adrenomedullin and Its Decoy Receptor Shape the Heart’s Lymphatic Highway

Deep inside the developing heart, a network of thin-walled vessels quietly drains fluid and ferries immune cells — and scientists have now identified the molecular switches that build it. In a study published in Nature Communications, a team led by Xidi Feng and Ching-Ling Lien of Children’s Hospital Los Angeles, working with Kenneth D. Poss at the Morgridge Institute for Research, shows that two genes, adrenomedullin a (adma) and its decoy receptor ackr3a, orchestrate the formation and function of cardiac lymphatic vessels in zebrafish. The findings reveal a previously underappreciated layer of control over lymphangiogenesis, the sprouting of new lymphatic vessels, and could inform strategies to manipulate lymphatic growth in injured or regenerating hearts.

The heart’s lymphatic system is far more than a passive drainage network. Cardiac lymphatic vessels regulate fluid homeostasis within the beating organ and clear immune cells from the tissue, keeping inflammation in check. When these vessels fail to form properly, fluid accumulates and immune responses run unchecked — problems that matter both during development and after injury. Yet the mechanisms that tell cardiac lymphatic endothelial cells, or LECs, where to grow and how to pattern themselves have remained murky. To crack the problem, the researchers turned to the zebrafish, a transparent model organism whose heart can be imaged live and which, remarkably, can regenerate damaged heart muscle — a feat mammals largely cannot perform.

The team’s first technical advance was spatial transcriptomics performed on the zebrafish heart at the single-cell level. This approach maps gene expression patterns onto intact tissue, allowing researchers to see not just which genes are active in cardiac LECs, but where those cells sit relative to their neighbors. The analysis revealed striking heterogeneity among cardiac LECs: rather than a uniform population, the heart’s lymphatic endothelium comprises distinct subpopulations with different gene expression profiles. Among the genes highlighted by this screen, one stood out — adrenomedullin a, or adma, which is mainly expressed in the epicardium, the thin outer layer of the heart, adjacent to the cardiac lymphatic vessels.

Adrenomedullin is a peptide signaling molecule with well-known roles in vascular biology, but its function in cardiac lymphatic development had not been pinned down. Because adma is expressed in the epicardium rather than in the LECs themselves, the finding suggested a paracrine mechanism: the epicardium secretes adrenomedullin, which then acts on nearby lymphatic endothelial cells to guide their growth. To test this, the researchers generated adma mutant zebrafish and examined their cardiac lymphatics in detail.

The results were dramatic. adma mutants developed edema — fluid accumulation throughout the body — and dilated outflow tracts, the vessel structures that carry blood away from the heart. Their cardiac lymphatic vessels were mis-patterned and reduced in number. Even more tellingly, the ventricular lymphatics — the lymphatic vessels covering the heart’s main pumping chamber — were dilated, with fewer sprouts, increased expression of lyve1b, a lymphatic endothelial marker gene, and altered composition of lymphatic subpopulations. Together, these phenotypes show that adrenomedullin signaling is required for cardiac lymphatic vessels to form correctly, to sprout normally, and to maintain their proper subpopulation balance during development.

The researchers then investigated the other side of the signaling equation. ackr3a encodes a decoy receptor for adrenomedullin — a receptor that binds the peptide but, rather than transmitting a signal, sequesters it and thereby dampens adrenomedullin signaling. When the team deleted ackr3a in zebrafish, the effect was the opposite of adma loss: lymphatic sprouting increased. This opposing pattern of phenotypes reveals a push-pull mechanism. The epicardium provides adrenomedullin to promote lymphatic growth, while the decoy receptor Ackr3a restrains that growth by mopping up excess peptide. The balance between the two determines how many lymphatic sprouts form and how the vessels pattern themselves around the heart.

The study’s scope extended beyond development into regeneration. When the zebrafish heart is injured, it mounts a regenerative response in which the epicardium reactivates and epicardium-derived cells populate the wound. The researchers found that during heart regeneration, adma and ackr3a are expressed in epicardium-derived cells within the wound — the same molecular pair deployed during development is redeployed in the adult injured heart. This co-expression suggests that adrenomedullin signaling helps coordinate the lymphatic response to cardiac injury, potentially linking lymphatic vessel growth to the broader regenerative program.

Immune cell dynamics provided another clue to the pair’s function. Neutrophils, the first responders of the innate immune system, are cleared from tissues by the lymphatic system. The researchers found that neutrophil clearance is reduced in adma mutants — consistent with defective lymphatic function — but increased in ackr3a mutants, consistent with enhanced lymphatic sprouting and activity. This mirror-image pattern of immune cell clearance reinforces the idea that adrenomedullin and its decoy receptor jointly regulate not only lymphatic vessel architecture but also lymphatic vessel function, specifically the vessels’ capacity to remove immune cells from the heart.

Technically, the study demonstrates the power of combining spatial transcriptomics with genetic perturbation in a regenerative model organism. By mapping gene expression in cardiac LECs at single-cell resolution and then deleting candidate genes one by one, the team could connect specific molecular signals to specific lymphatic phenotypes — from sprout number to vessel dilation to subpopulation composition. The identification of distinct lymphatic subpopulations within the heart adds a new dimension to lymphatic biology, suggesting that cardiac LECs are specialized for different tasks and that signals like adrenomedullin help maintain the balance among these specialized states.

For the broader scientific community, the findings open several avenues. If adrenomedullin signaling promotes cardiac lymphatic growth while Ackr3a restrains it, then pharmacologically manipulating this axis — enhancing adrenomedullin signaling or blocking the decoy receptor — might stimulate lymphatic vessel formation in settings where lymphatic function is impaired, such as after cardiac injury or in lymphatic vascular diseases. Conversely, blocking the pathway might restrain excessive lymphatic growth. Because the zebrafish heart regenerates, the model provides a platform for testing whether tuning adrenomedullin signaling improves regenerative outcomes — a question the field can now pursue with the molecular targets in hand. The study, published as an open-access article in Nature Communications on 17 October 2026, was supported by the CIRM Scholar Award, the Heart Ambassadors Intramural Grant, and NIH NHLBI funding, and involved collaborators including J. Gage Crump at the University of Southern California and Young-Kwon Hong at Harvard Medical School.

Subject of Research: Adma and Ackr3a regulate cardiac lymphatic vessel formation and function during heart development and regeneration

Article Title: Adma and Ackr3a regulate cardiac lymphatic vessel formation and function during heart development and regeneration

Article References: Feng, X., Chen, H.-Y., Sun, Y., Sun, F., Yan, S., Kapuria, S., Rodriguez, R., Gamba, L., Crump, J. G., Hong, Y.-K., Poss, K. D., & Lien, C.-L. (2026). Adma and Ackr3a regulate cardiac lymphatic vessel formation and function during heart development and regeneration. Nature Communications. https://doi.org/10.1038/s41467-026-78353-8

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78353-8

Keywords: Adma, Ackr3a, regulate, cardiac, lymphatic, vessel, formation, function, during, heart, development, regeneration