Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis

Dobner, S.; Kleissl, L.; Toth, F.; Paxton, R.; Yordanova, I.; Brazdilova, K.; Vanluyten, C.; Aizenshtadt, A.; Toth, H.; Burton, J.; Kopf, A.; Belyaeva, V.; Ferencevic, K.; Al-Nuaimi, D. A.; Rendeiro, A. F.; Bock, C.; Kalucka, J.; Krauss, S.; Osmanagic-Myers, S.; Ceulemans, L. J.; Stary, G.; Abdel Fattah, A. R.; de Rooij, L. P.

doi:10.1101/2025.08.18.669055

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bioRxiv · 10.1101/2025.08.18.669055

Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis

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Abstract

Endothelial cells (ECs) are critical regulators of vascular function and exhibit specialized, organ-specific roles across tissues. During aging, these cells become dysfunctional, resulting in increased susceptibility to cardiovascular disease and its associated mortality. While single-cell transcriptomics studies have revealed extensive endothelial heterogeneity across tissues and conditions, a comprehensive atlas of human EC transcriptomes over the course of the adult human lifespan is still lacking. Here, we present the Human Aging Endothelial Cell Atlas (HAECA), a harmonized single-cell transcriptomic compendium of over 375,000 ECs from 12 human tissues throughout adulthood. Using HAECA, we identified age-associated transcriptional shifts, including a decline in angiogenic gene expression in venous ECs and widespread alterations in extracellular matrix (ECM)- and mechanotransduction-associated pathways. We validated these findings in aging human skin and further uncovered a p21-linked transcriptional program in ECs, confirmed in both in vitro and in vivo models and linked to cellular senescence. Together, our study provides a high-resolution transcriptome reference across spatial as well as temporal axes of the human endothelium.

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Dobner, S., Kleissl, L., Toth, F., Paxton, R., Yordanova, I., Brazdilova, K., Vanluyten, C., Aizenshtadt, A., Toth, H., Burton, J., Kopf, A., Belyaeva, V., Ferencevic, K., Al-Nuaimi, D. A., Rendeiro, A. F., Bock, C., Kalucka, J., Krauss, S., Osmanagic-Myers, S., Ceulemans, L. J., Stary, G., Abdel Fattah, A. R., de Rooij, L. P.. 2025-08-19. Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis. https://doi.org/10.1101/2025.08.18.669055

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