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

Endothelial cells (ECs) are critical regulators of vascular function and exhibit tissue-specialized roles. During aging, these cells become dysfunctional, resulting in increased susceptibility to cardiovascular disease. Although single-cell transcriptomics has revealed extensive endothelial heterogeneity, a comprehensive atlas of human EC transcriptomes over the course of the adult human lifespan has been 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. We identified age-associated transcriptional shifts, including a decline in angiogenic gene expression in venous ECs and widespread alterations in extracellular matrix and mechanotransduction-associated signatures. Furthermore, we uncovered a p21-linked transcriptional program in ECs, which we linked to cellular senescence in both in vitro and in vivo models. Together, our study provides a high-resolution transcriptomic reference of the human endothelium across tissues and age.