Integrative single-cell analysis reveals endothelial diversity in the vasa vasorum of human atherosclerosis

Microvessels within atherosclerotic plaques are crucially involved in disease progression. Here, we generated a transcriptomic atlas of human atherosclerosis at single-cell resolution, encompassing 17,367 vascular endothelial cells (VECs) from five scRNA-seq studies, and verified key morphological characteristics using histology. SULF1+ arterial endothelial cells (ArtECs) represented the primary subcluster undergoing endothelial-to-mesenchymal transition (EndMT). Capillary-like endothelial cells (CapECs) were identified as primary mediators of angiogenesis, and a trajectory model illustrated the transition between tip and stalk cells, with subclusters of ArtECs and CapECs predominantly expressing CXCL12, thereby driving the CXCL12/CXCR4 signaling axis. The largest plaque EC cluster, exhibiting the most heterogeneity, was found among post-capillary venule endothelial cells (VenECs), particularly ACKR1highNR2F2low VenECs, which displayed distinct inflammatory transcriptional signatures characterized by adhesion molecules and chemokines. Overall, this atlas of atherosclerosis underscores endothelial heterogeneity and identifies SULF1+ ArtECs and VenECs as potential therapeutic targets for EndMT and leukocyte recruitment, respectively. Single-cell analysis of human atherosclerosis revealed distinct endothelial cell subclusters associated with inflammation, angiogenesis, and endothelial-to-mesenchymal transition.