Molecular determinants of cardiac lymphatic dysfunction in a chronic pressure-overload model

Cardiac lymphatic alterations and insufficient lymphatic drainage have been found in cardiovascular diseases (CVDs). To unravel the mechanisms underlying lymphatic dysfunction, we applied single-cell (sc) analyses in murine heart failure (HF) models. Transaortic constriction (TAC) in C57BL/6J and BALB/c mice modeled chronic pressure -overload-induced cardiac hypertrophy and HF, respectively. Cardiac lymphatic (LEC) and blood vascular endothelial cells (BEC) were analyzed by scRNAseq, and targets validated by immunohistochemistry and human LEC cultures. While LEC profiles were comparable between strains in healthy mice, we found expansion of lymphatic capillaries and loss of valves post-TAC only in BALB/c. Differentially expressed gene (DEG) analysis revealed a reduction post-TAC only in BALB/c of lymphatic junctional components. Conversely, LEC expression of immune cell cross-talk mediators was mostly preserved post-TAC. Interestingly, around 35% of DEGs identified in cardiac LECs post-TAC were similarly altered in interleukin (IL)1β-stimulated human LECs. In conclusion, loss of lymphatic valves and dysregulated lymphatic barrier may underlie poor drainage capacity during pressure-overload-induced HF, despite potent lymphangiogenesis and preserved LEC immune attraction. Our work provides tractable targets to restore lymphatic health in CVDs.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2025-12-11
DOI
https://doi.org/10.1038/s44321-025-00345-w
Citations
1
Primary Topic
Lymphatic System and Diseases
Type
article
Field-Weighted Citation Impact
1.05

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article

Molecular determinants of cardiac lymphatic dysfunction in a chronic pressure-overload model

Alma Zernecke, Gaëtan Riou, Théo Lemarcis, Damien Schapman et al.
1 citations
EMBO Molecular Medicine
Lymphatic System and Diseases
1.05
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Molecular determinants of cardiac lymphatic dysfunction in a chronic pressure-overload model

Alma Zernecke, Gaëtan Riou, Théo Lemarcis, Damien Schapman, Sophie Candon, Ebba Bråkenhielm, Céline Derambure, Hélène Dauchel, Virginie Tardif, Coraline Heron, David Godefroy, Ch Thuilliez, Océane Laguerre, Manon Valet, Benjamin Bourgeois, Anaïs Dumesnil, Caroline Bérard, Claire Valentin
article en
1 citations

Abstract

Cardiac lymphatic alterations and insufficient lymphatic drainage have been found in cardiovascular diseases (CVDs). To unravel the mechanisms underlying lymphatic dysfunction, we applied single-cell (sc) analyses in murine heart failure (HF) models. Transaortic constriction (TAC) in C57BL/6J and BALB/c mice modeled chronic pressure -overload-induced cardiac hypertrophy and HF, respectively. Cardiac lymphatic (LEC) and blood vascular endothelial cells (BEC) were analyzed by scRNAseq, and targets validated by immunohistochemistry and human LEC cultures. While LEC profiles were comparable between strains in healthy mice, we found expansion of lymphatic capillaries and loss of valves post-TAC only in BALB/c. Differentially expressed gene (DEG) analysis revealed a reduction post-TAC only in BALB/c of lymphatic junctional components. Conversely, LEC expression of immune cell cross-talk mediators was mostly preserved post-TAC. Interestingly, around 35% of DEGs identified in cardiac LECs post-TAC were similarly altered in interleukin (IL)1β-stimulated human LECs. In conclusion, loss of lymphatic valves and dysregulated lymphatic barrier may underlie poor drainage capacity during pressure-overload-induced HF, despite potent lymphangiogenesis and preserved LEC immune attraction. Our work provides tractable targets to restore lymphatic health in CVDs.

EMBO Molecular MedicineVol. 18(1)
Centre National de la Recherche Scientifique (FR), Inserm (FR), Différenciation et Communication Neuronale et Neuroendocrine (FR), Normandie Université (FR), Laboratoire d'Informatique, du Traitement de l'Information et des Systèmes (FR), Universitätsklinikum Würzburg (DE), Université de Rouen Normandie (FR)
Région Normandie
Openalex Percentile: Top 15%
Lymphatic System and Diseases
1.05
DOIOpen Access PDFOpenAlex
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