Uncovering the transcriptional hallmarks of endothelial cell aging via integrated single-cell analysis (MERFISH dataset)

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.内皮细胞（Endothelial cells, ECs）是血管功能的核心调控因子，在各组织中发挥器官特异性的特化功能。在衰老进程中，这类细胞会发生功能失调，导致个体罹患心血管疾病及其相关死亡的风险显著升高。尽管单细胞转录组学研究已揭示了不同组织与生理病理状态下内皮细胞的广泛异质性，但目前仍缺乏覆盖成人全生命周期的人类内皮细胞转录组综合图谱。本研究构建了人类衰老内皮细胞图谱（Human Aging Endothelial Cell Atlas, HAECA），这是一套标准化整合了成人阶段12种人体组织共逾37.5万个内皮细胞的单细胞转录组汇编数据集。借助HAECA数据集，我们鉴定出了与衰老相关的转录组特征变化，包括静脉内皮细胞中血管生成基因表达的下调，以及细胞外基质（extracellular matrix, ECM）和机械转导相关通路的广泛重塑。我们在衰老人体皮肤样本中验证了上述发现，并进一步揭示了内皮细胞中与p21相关的转录调控程序，该程序在体外（in vitro）与体内（in vivo）模型中均得到验证，且与细胞衰老紧密关联。综上，本研究为人类内皮细胞构建了覆盖空间与时间维度的高分辨率转录组参考图谱。