SETD2 Improves Endothelial Function and Angiogenesis in Diabetic Hindlimb Ischemia Via Activating ANGPT2-PI3K/AKT...

Vascular endothelial dysfunction serves as a key pathological basis for diabetic vascular complications. Enhancing endothelial function and promoting angiogenesis are therefore critical strategies in the treatment of diabetic lower hindlimb ischemia (HLI). SETD2 is the primary methyltransferase for H3K36 trimethylation (H3K36me3) and is involved in vascular development, but its role in diabetes-associated endothelial dysfunction remains unknown. This study aimed to investigate the function and underlying mechanism of SETD2 in endothelial cells under diabetic conditions and in the context of diabetic HLI. A diabetic mouse model was established in endothelial-specific conditional SETD2 knockout (SETD2^ECKO) mice using a high-fat diet combined with streptozotocin (HFD/STZ) injection. After a single ligation of the common femoral artery in these mice, we observed that endothelial-specific conditional deletion of SETD2 significantly impaired blood flow recovery and reduced capillary density in the ischemic gastrocnemius muscle. In vitro, human umbilical vein endothelial cells (HUVECs) were exposed to high glucose and palmitate (HG/PA) to simulate a diabetic microenvironment. It was found that HG/PA treatment down-regulated the expression of SETD2 and H3K36me3 in HUVECs. Functional studies revealed that SETD2 over-expression alleviated, whereas SETD2 inhibition aggravated, HG/PA-induced impairments in endothelial proliferation, migration, and tube formation. Mechanistically, SETD2 was found to positively regulate the expression of ANGPT2. KEGG enrichment analysis and Western blot validation indicated that SETD2 modulates the PI3K-AKT signaling pathway. Notably, exogenous ANGPT2 supplementation partially rescued endothelial dysfunction and restored AKT phosphorylation in SETD2-inhibited cells under HG/PA conditions. In conclusion, SETD2 preserves endothelial function and promotes angiogenesis by up-regulating ANGPT2 and subsequently activating the PI3K-AKT signaling axis. The SETD2-ANGPT2-PI3K/AKT pathway may represent a promising therapeutic target for the treatment of diabetic vascular complications.