Endothelial Regeneration of Large Vessels Is a Biphasic Process Driven by Local Cells with Distinct Proliferative Capacities

The cellular and mechanistic bases underlying endothelial regeneration of adult large vessels have proven challenging to study. Using a reproducible in vivo aortic endothelial injury model, we characterized cellular dynamics underlying the regenerative process through a combination of multi-color lineage tracing, parabiosis, and single-cell transcriptomics. We found that regeneration is a biphasic process driven by distinct populations arising from differentiated endothelial cells. The majority of cells immediately adjacent to the injury site re-enter the cell cycle during the initial damage response, with a second phase driven by a highly proliferative subpopulation. Endothelial regeneration requires activation of stress response genes including Atf3, and aged aortas compromised in their reparative capacity express less Atf3. Deletion of Atf3 reduced endothelial proliferation and compromised the regeneration. These findings provide important insights into cellular dynamics and mechanisms that drive responses to large vessel injury. [Display omitted] •Regeneration of the endothelial lining is mediated by cells flanking the injury•Endothelial repair does not require circulation of tip/stalk specification•Cells driving regeneration express a cohort of stress response genes•Atf3 is required for regeneration of the endothelial lining of large arteries Quiescent endothelial cells are able to mount a robust mitotic response even in the presence of pulsatile and high-velocity blood flow. McDonald et al. showed that regeneration of aortic inner lining involves a subset of cells with hidden proliferative capacity that undergo rapid and significant transcriptional changes.