CD38⁺ endothelial remodeling marks spatially patterned vasculopathy in rapidly advancing periodontitis and peri-implantitis

Oral inflammatory diseases affect nearly half of all humans, yet mechanisms underlying rapidly-destructive inflammation remain poorly understood. We compared peri-implantitis with moderate- and high-grade periodontitis using integrated microbial and single-cell sequencing (>967,169-cells; single-cell RNA-seq, spatial proteotranscriptomics). Laser capture microdissection with compartmental microbiome analysis revealed reduced bacterial load and diversity in peri-implantitis. Expansion of the Human Periodontal Atlas with peri-implantitis single-cell RNA-seq data (36-samples; 121,395 cells) identified CD34+ vascular endothelial cell (VEC) rarefaction and oxidative stress, hypoxia, and NAD⁺ metabolism-associated transcriptional programs enriched in a TNFRSF6B⁺/ICAM1⁺ post-capillary venule (PC-VEC) subpopulation. NAD⁺-consuming ectoenzyme CD38 was selectively enriched and orthogonally confirmed by spatial transcriptomics (6-samples; 283,377-cells) and proteomics (23-samples; 562,397-cells). Spatial neighborhood analyses demonstrated CD38⁺-high PC-VEC expansion, closer proximity, and higher IL16–CD4 T cell signaling in peri-implantitis. Matched high-grade periodontitis biopsies confirmed spatially restricted CD38⁺-VECs despite similar microbial burden, identifying endothelial vasculopathy underlying rapidly advancing oral inflammation and a potential therapeutic axis. Oral inflammatory diseases affect nearly half of all people, yet rapid progression drivers are unclear. The study identified CD38+ endothelial cell dysfunction and vascular remodeling as key features of aggressive oral inflammation.