Endothelial Sestrin2 Coordinates Multiple Protective Pathways to Maintain Angiogenic Function in Diabetes-Associated...

Area of Science:

• Endocrinology and Metabolism
• Cellular Biology
• Vascular Biology

Background:

• Diabetes mellitus causes widespread vascular complications, leading to high mortality.
• Methylglyoxal (MGO), a glycolysis byproduct, significantly contributes to diabetic vascular dysfunction.
• Sestrin2 (SESN2) is a key cellular stress response regulator, but its role in diabetic endothelial cells is unclear.

Purpose of the Study:

• To investigate the function of Sestrin2 (SESN2) in maintaining endothelial cell angiogenic function under methylglyoxal (MGO)-induced stress.
• To elucidate the molecular mechanisms by which SESN2 influences cellular homeostasis and vascular health in a diabetic context.

Main Methods:

• Utilized loss-of-function and gain-of-function approaches in EA.hy926 endothelial cells.
• Assessed endothelial cell angiogenic capacity, proliferation, and invasive potential under MGO stress.
• Analyzed the involvement of NRF2/HO-1, VEGF-C, AKT/mTOR, and MAPK signaling pathways.

Main Results:

• SESN2 overexpression preserved endothelial cell angiogenesis, proliferation, and invasion under MGO stress.
• SESN2 silencing exacerbated MGO-induced impairment of angiogenic capacity.
• SESN2 activated the NRF2/HO-1 antioxidant pathway, enhanced VEGF-C expression, balanced AKT/mTOR signaling, and reduced p38/ERK1/2 activation.

Conclusions:

• SESN2 is a critical regulator of endothelial cell homeostasis and angiogenesis under MGO-induced stress.
• SESN2's dual action on antioxidant pathways and angiogenesis suggests therapeutic potential for diabetic vascular complications.
• Targeting SESN2 may offer a novel strategy to improve outcomes for diabetic patients.