CD4 ⁺ Tregs Drive Post‐Ischemic Sprouting Angiogenesis via Endothelial YY1/MAML1 Reactivation

ABSTRACT Microvascular complications of diabetes are chronic diseases of small vessels. We previously found that CD4 ⁺ regulatory T‐cells (Tregs) are markedly reduced in type 2 diabetes (T2D) after ischemic injury in both mice and humans, and that Treg deficiency in immunodeficient mice impairs vascular regeneration. However, the mechanisms by which Tregs protect against diabetic vascular disease remain unclear. Here, we demonstrate that endothelial cells (ECs) upregulate the transcription factor YY1 during post‐ischemic vascular regeneration, but this response is blunted in diabetic ECs. Endothelial‐specific deletion of YY1 leads to defective vascular regeneration following ischemia. Mechanistically, YY1 binds to the MAML1 promoter at regions enriched for H3K4me3 and H3K27ac. YY1 activates MAML1 transcription, likely by recruiting H3K4me3 writers (SETD1A, MLL1, MLL2) and their scaffold WDR5 within the COMPASS complex, together with the H3K27ac writer p300. Functionally, Tregs enhance vascular regeneration through paracrine signaling even in T2D mice. Adoptive Treg transfer restores regenerative capacity by reactivating the endothelial YY1/MAML1 axis. These findings identify a Treg‐YY1‐MAML1 pathway as a key regulator of endothelial function and vascular repair, offering mechanistic insight into how Tregs promote tissue regeneration in diabetes‐associated microvascular dysfunction.