Red blood cells drive blood vessel damage in diabetes by exporting toxic vesicles

A new study discovers how to release diabetic red blood cells toxic packages that damage blood vessels, which reveals a promising path to prevent serious complications.

EVs derived from RBCs from patients with T2D are absorbed by the endothelium and the endothelial-dependent relaxation by an EV-mediated transfer of the Prooxidant enzyme ARG1. Proteoglycan Remodeling is a main event that promotes EV recording and can offer goals that can serve as biomarkers of diseases and/or personalized therapies for blocking EV recording. RBC-EVs are also involved in diabetes-related comorbidities, namely hypercoagulability, myocardial infarction and vascular dementia. Blood transfusion of patients with cardiovascular risk factors represents a potential problem, given the transfer of RBC-EVs and subsequent endothelial dysfunction in the recipient patient.

Type 2 Diabetes Mellitus (T2DM) is associated with many invalidating and often fatal vascular complications, including stroke, heart attacks, gangrene of limbs, loss of vision and kidney failure. Reduced endothelial function, caused by oxidative stress, is based on these events. The source of this stress has remained elusive.

A recent comment published in the Journal of Clinical Investigation explains the importance of a study by Collado et al. (((J Clin Invest. 2025; 135 (10): E180900) that demonstrates the central role of red blood cells (RBCs) in this phenomenon. This can promote the development of molecular therapies to prevent such complications.

Introduction

Until recently, most scientists thought that vascular dysfunction in T2DM was caused by endogenous endothelial factors. It now seems that it is caused by external factors.

One of these factors, an important contribution, are the RBCs. They improve the level of the enzyme Arginase-1 (ARG1), which promotes oxidation and increases the levels of reactive oxygen species (ROS) in the endothelium. This in turn reduces the functioning of the vasodilic molecule, endothelial nitrogen oxide (NO).

T2DM RBC-EV Release

In the research into the referred, the scientists discovered that RBCs separate extracellular blisters (EVs) at T2DM patients with ARG1. These trips to and are recorded by the vascular endothelial cells. The resulting increase in endothelial ARG1 activity induces vascular damage with Protean manifestations.

Diabetic RBCs release fewer EVs than healthy, but only the first comes in the endothelium. RBCs shed a fifth of their membrane area during their 120-day lifespan, so the mere release of RBC-EVs is not a marker for diseases. The change in composition is more important, involving changes in EV-Membraanhparansulfate-Proteoglycans (eg Syndecan-4, CD44).

These changes facilitate the intake of EV. A better understanding of this can help develop treatments aimed at the underlying mechanism of vascular disease at T2DM, such as inhibitors of remodeling of proteoglycan. Such work can also help identify biomarkers of endotheli diseases.

EV recording and vasoconstriction

Endothelial intake of RBC-EVs in T2DM patients results in reduced endothelial vascular relaxation compared to those of the RBCs of healthy patients.

The endothelial function improved when EV uptake was prevented by heparin, which confirms the role of EV absorption in endothelial dysfunction. Heparin, a natural glycosaminoglycan, also confirms the importance of proteoglycan changes in EV recording, especially because EVs express proteins, including heparansulfate proteoglycans.

It is important that the proteomic analysis of the study revealed other disrupted ROS-related proteins in diabetic RBC-EVs, suggesting that ARG1 is part of a broader oxidative network.

Again, Arg1 inhibitor AB prevented Ros after exposure to RBC. In addition, Muisaorta rings showed endothelial dependent relaxation of the vascular wall despite being exposed to T2DM RBCs, in the presence of ABH. This provides evidence for the causal role of EV recording in oxidative endothelial stress.

However, the actual investigation of the endothelium exposed to T2DM RBC-EV ARG1 in a living animal would, however, reflect actual fabric exposures in T2DM.

Genetic manipulations to silence or beat endogenic ARG1 in endothelial cells confirmed that exogenous causes oxidative stress instead of endothelial ARG1. This previously confirmed work in which the removal of endothelial ARG1 in mice endothelial dysfunction did not reverse.

RBC-EVs from T2DM and healthy people have similar ARG1 levels. That is why the increased EV -recording endothelial damage at T2DM causes, instead of EV recipient. How the blood sugar level influences the absorption of endothelial EV in T2DM is still unclear.

RBC-EVs and vascular diseases

RBC-EVs also play a role in inducing hypercoagulability of blood, heart attacks and vascular dementia in T2DM.

RBC-EVs in T2DM, for example, contain tissue self-factor, often in addition to exposed phosphatidyl serin tests, which promote clotting. RBC-EVs predict poorer results in patients with ST-Elevation Myocardinfarct (STEMI)-the most common type of heart attack-after primary percutaneous coronary intervention (PCI), a procedure intended to restore blood flow.

RBCs, in particular from diabetic donors, hand over EVs during storage, which can worsen risks when they are transfused into recipients.

Again, A-Synuclein, a protein that is found in neuro inflammation and dementia, is almost 1,000-time raised in RBC-EVs compared to cerebrospinal fluid. These EVs continue to exist in the circulation and cross the blood-brain barrier, causing brain inflammation. This can explain the injury of the capillaries and neurons of the brain in T2DM, causing the faster development of cognitive impairment and dementia.

Transfusing blood of such patients may induce endothelial dysfunction and other side effects in the recipient. This deserves more attention, especially when the blood of people older than 65 or smokers, who have an increased cardiovascular risk.

Conclusions

“Proof of this study makes us believe that the solution to the problem could not be in the vascular endothelium, but in the blood.” The pathbreaking study points both to the mechanism of endothelial dysfunction in T2DM and suggests new molecular goals to prevent their occurrence.