Key result
Physiological aging and cardiovascular diseases remodel human cardiac lymphatic endothelial cells through distinct changes in cellular state and microenvironmental signaling, and endothelial Acvr2a deletion preserved cardiac function in doxorubicin-treated mice.
Why the study?
Human cardiac lymphatic endothelial cell heterogeneity changes with physiological aging and cardiovascular disease remain poorly defined, limiting understanding of their roles in tissue homeostasis and remodeling.
Does physiological aging and cardiovascular disease distinctively remodel human cardiac lymphatic endothelial cell states, and does endothelial Acvr2a deletion preserve cardiac and lymphatic function during doxorubicin injury?
Does physiological aging and cardiovascular disease distinctively remodel human cardiac lymphatic endothelial cell states, and does endothelial Acvr2a deletion preserve cardiac and lymphatic function during doxorubicin injury?
Cardiac lymphatic endothelial cells undergo distinct structural and regulatory remodeling during physiological aging and cardiovascular disease, and targeting the BMP/activin-ACVR2A signaling pathway may preserve cardiac lymphatic architecture and function during doxorubicin injury.
Endothelial Acvr2a deletion preserved function in doxorubicin mice; hypothesis-generating for BMP pathway targeting in chemotherapy cardiomyopathy, pending human trials.
Aims Cardiac lymphatic endothelial cells (LECs) regulate tissue homeostasis, immune trafficking, and remodeling, but how human cardiac LEC heterogeneity changes with physiological aging and cardiovascular disease remains poorly defined. We sought to define age- and disease-associated LEC states, their regulatory and microenvironmental programs, and the functional relevance of selected pathways. Methods and results We integrated human cardiac single-nucleus transcriptomic datasets spanning physiological aging, dilated and hypertrophic cardiomyopathy, doxorubicin-associated cardiomyopathy, and heart failure with preserved ejection fraction. Aging redistributed LECs among pre-existing states, with expansion of a homeostatic immune-surveillance state and loss of cytokine-responsive and polarity-associated states. Cardiovascular diseases showed a distinct trajectory, with depletion of a non-failing homeostatic state and expansion of shared and disease-associated remodeling states. SCENIC and NicheNet/MultiNicheNet identified state-specific regulatory programs and disease-dependent signaling networks, with recurrent BMP/TGF-β/activin-family signaling. ACVR2A was prioritized in human doxorubicin-associated cardiomyopathy; endothelial Acvr2a deletion in aged doxorubicin-treated mice was associated with improved cardiac function and increased open cardiac lymphatic vessels. Independent human spatial transcriptomic analyses supported selected aging- and disease-associated programs. Conclusion Physiological aging and cardiovascular disease remodel cardiac LECs through distinct changes in cellular state, transcriptional regulation, and microenvironmental signaling. Aging is associated with redistribution and reduced representation of specialized LEC programs, whereas cardiovascular diseases redirect LECs through disease-associated signaling environments, highlighting context-dependent remodeling of the cardiac lymphatic endothelium across aging and disease. Translational Perspective Cardiac lymphatic dysfunction may contribute to impaired immune resolution and myocardial remodeling, but human disease-associated LEC biology remains poorly understood. We identify distinct LEC remodeling trajectories during physiological aging and cardiovascular disease and identify age-associated loss of specialized cytokine-responsive and structural LEC programs. Disease-specific microenvironmental analyses nominate actionable signaling pathways, while endothelial Acvr2a deletion preserves cardiac lymphatic remodeling and improves cardiac function following doxorubicin injury. These findings highlight LEC state remodeling and disease-associated signaling as potential targets for preserving cardiac lymphatic function during aging and cardiovascular disease.
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Chen et al. (2026) studied Physiological aging and cardiovascular disease (DCM, HCM, DoxCM, HFpEF). Physiological aging and cardiovascular disease vs. Young and non-failing hearts was evaluated on Changes in cardiac lymphatic endothelial cell (LEC) heterogeneity, transcriptional regulation, and microenvironmental signaling. Physiological aging and cardiovascular diseases remodel human cardiac lymphatic endothelial cells through distinct changes in cellular state and microenvironmental signaling, and endothelial Acvr2a deletion preserved cardiac function in doxorubicin-treated mice.
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