Red Blood Cells Linked to Vascular Damage in Type 2 Diabetes: Study

Led by Aida Collado Sanchez and her team at the Karolinska Institutet in Stockholm, the research explores how RBCs in type 2 diabetes mellitus (T2DM) contribute to endothelial dysfunction—an early marker for various vascular complications, including heart attacks, strokes, and kidney disease. Despite producing fewer EVs than those from healthy individuals, diabetic RBCs showed increased vesicle uptake by endothelial cells. This uptake impaired the ability of blood vessels to relax, a key feature of healthy vascular function.

The researchers demonstrated that this dysfunction could be significantly reduced by blocking arginase activity or mitigating oxidative stress. Their findings suggest that RBC-derived EVs transfer arginase-1 into the endothelial cells, triggering oxidative mechanisms that disrupt the nitric oxide pathway, which is essential for vascular dilation.

The study challenges the long-held belief that endothelial dysfunction in diabetes is primarily due to intrinsic defects within the endothelial cells. Instead, it positions RBC-derived vesicles as external instigators of vascular injury. A better understanding of the mechanisms involved in EV uptake, particularly changes to proteoglycans like syndecan-4 and CD44 on the EV surface, could help in developing targeted interventions.

Further supporting the findings, proteomic analysis of diabetic RBC-EVs revealed elevated levels of proteins linked to oxidative stress. Treatment with an arginase-1 inhibitor, ABH, prevented the spike in reactive oxygen species and preserved normal vessel relaxation in mouse models, even after exposure to diabetic RBC-EVs.

Genetic studies in mice confirmed that this damaging process stems from externally delivered arginase-1 rather than the endothelial cells’ enzyme. Even when the internal production of arginase-1 was silenced, the vesicle-transferred enzyme was sufficient to provoke oxidative stress.

Beyond vascular damage, the study touches upon broader implications of RBC-EVs in diabetes-related complications. These vesicles carry pro-thrombotic markers like tissue factor and phosphatidylserine, which may contribute to increased clotting risk in heart attack patients. Additionally, EVs containing the protein α-synuclein, which plays a role in neurodegenerative diseases, could pass into the brain and trigger inflammation, possibly explaining the higher risk of dementia in diabetics.

“This study suggests that the problem may not lie within the blood vessels themselves, but rather in the blood,” the authors noted. Their work clarifies the cellular mechanisms behind diabetes-induced vascular damage and paves the way for novel therapies aimed at blocking EV uptake or neutralizing their harmful cargo.

Reference:

Erythrocyte-derived extracellular vesicles induce endothelial dysfunction through arginase-1 and oxidative stress in type 2 diabetes. Aida Collado, … , Zhichao Zhou, John Pernow. Published March 20, 2025. Citation Information: J Clin Invest. 2025;135(10):e180900. https://doi.org/10.1172/JCI180900.