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

Area of Science:

• Cardiovascular Biology
• Immunology
• Endocrinology

Background:

• Microvascular complications are chronic issues in diabetes affecting small blood vessels.
• CD4+ regulatory T-cells (Tregs) are reduced in type 2 diabetes (T2D) post-ischemic injury, and their deficiency impairs vascular regeneration.
• The precise mechanisms by which Tregs protect against diabetic vascular disease are not fully understood.

Purpose of the Study:

• To elucidate the mechanisms by which Tregs protect against diabetic vascular disease.
• To investigate the role of the transcription factor YY1 in endothelial cells during vascular regeneration in diabetes.
• To identify the molecular pathway linking Tregs to improved vascular repair in T2D.

Main Methods:

• Investigated endothelial cell (EC) transcription factor YY1 expression in post-ischemic vascular regeneration in diabetic mice and humans.
• Utilized endothelial-specific YY1 deletion models to assess its role in vascular repair.
• Examined the molecular interaction of YY1 with the MAML1 promoter and epigenetic modifications (H3K4me3, H3K27ac).
• Assessed the effect of adoptive Treg transfer on vascular regeneration and the YY1/MAML1 axis in T2D mice.

Main Results:

• Endothelial cells (ECs) upregulate YY1 during vascular regeneration, but this is blunted in diabetic ECs.
• Endothelial-specific YY1 deletion results in defective vascular regeneration post-ischemia.
• YY1 activates MAML1 transcription by interacting with its promoter and recruiting epigenetic modifiers.
• Tregs enhance vascular regeneration via paracrine signaling in T2D mice.
• Adoptive Treg transfer restores regenerative capacity by reactivating the endothelial YY1/MAML1 axis.

Conclusions:

• Identified a novel Treg-YY1-MAML1 pathway critical for endothelial function and vascular repair.
• This pathway is a key regulator of tissue regeneration in diabetes-associated microvascular dysfunction.
• Restoring the Treg-YY1-MAML1 axis represents a potential therapeutic strategy for diabetic vascular complications.