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 ACKR1^highNR2F2^low 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.