Erythrocyte-derived extracellular vesicles induce endothelial dysfunction through arginase-1 and oxidative stress in type 2 diabetes.

Summary

Using RBC-derived extracellular vesicles from T2D patients, the authors show that EV cargoed arginase-1 is transferred to endothelial cells, increasing oxidative stress and impairing endothelium-dependent relaxation. Inhibition of arginase (within EVs or vascular) or oxidative stress mitigated dysfunction, implicating RBC-EVs as key mediators of diabetic endothelial injury.

Key Findings

• T2D RBC-derived EVs are taken up more avidly by endothelial cells despite lower EV production.
• T2D RBC-EVs impair endothelium-dependent relaxation; arginase inhibition (in EVs or vessel) and antioxidant strategies attenuate dysfunction.
• Arginase-1 is present in RBC-EVs and increases in endothelial cells after exposure, even with endothelial Arg1 mRNA silencing and in Arg1-deficient endothelium.
• Mechanism involves EV transfer of arginase-1 leading to oxidative stress and endothelial dysfunction.

Clinical Implications

Arginase-1 and EV-mediated signaling emerge as therapeutic targets to improve endothelial function in T2D; arginase inhibitors or strategies reducing RBC-EV uptake could complement standard cardiometabolic care.

Limitations

• Clinical donor sample size and heterogeneity are not detailed in the abstract; translational dosing and pharmacology require further study.
• Predominantly ex vivo/in vitro mechanistic work; in vivo therapeutic modulation of EV pathways was not reported.

Future Directions

Evaluate arginase inhibition and EV uptake blockade in vivo for vascular endpoints in T2D, and test circulating RBC-EV arginase-1 as a biomarker of endothelial risk.