Circulating small extracellular vesicles mediate vascular hyperpermeability in diabetes

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by elevated blood sugar levels. One of its hallmark complications is vascular hyperpermeability, which can lead to cognitive impairment due to dysfunction of the cerebrovascular endothelium. Recent research has focused on understanding how small extracellular vesicles (sEVs) circulating in the bloodstream may contribute to this pathogenic disruption of the vascular barrier in individuals with diabetes.

Researchers at the Toronto General Hospital Research Institute sought to investigate whether sEVs isolated from diabetic individuals exhibit phenotypic changes that promote disruption of the endothelial cell (EC) barrier. Using both mouse models of T2DM and samples from diabetic human patients, the researchers characterized the composition and effects of sEVs on endothelial barrier function. Intravital imaging techniques were employed to visualize vascular permeability in live mice, while functional experiments elucidated the molecular pathways involved in sEV-induced hyperpermeability.

The study revealed several key findings. Firstly, diabetic mice exhibited increased vascular leakiness in the brain, which was replicated when sEVs from diabetic mice were injected into non-diabetic mice. Analysis of sEV populations from diabetic individuals showed elevated levels and larger sizes compared to non-diabetic controls. Functionally, sEVs from diabetic sources induced rapid and sustained disruption of the EC barrier without triggering inflammation.

Proteomic analysis of sEVs and recipient ECs highlighted alterations in MAPK/MAPK kinase (MEK) and Rho-associated protein kinase (ROCK) pathways, as well as changes in cell-cell junctions and actin dynamics. Experimental validation confirmed the involvement of these pathways in sEV-induced hyperpermeability. Importantly, treatment with proteinase K or inhibitors targeting MEK or ROCK mitigated the hyperpermeability-inducing effects of diabetic sEVs, suggesting potential therapeutic strategies.

The findings of this study shed light on a novel mechanism by which diabetes induces vascular dysfunction and cognitive decline. By elucidating the role of sEVs in promoting vascular hyperpermeability through MEK/ROCK pathway activation, the study provides valuable insights into the pathogenesis of diabetic complications. Moreover, it highlights the potential of targeting sEV-associated proteins as a therapeutic approach to mitigate vascular dysfunction in diabetes.

This study advances our understanding of the intricate interplay between diabetes, sEVs, and vascular dysfunction. By uncovering the mechanisms underlying sEV-induced hyperpermeability, the research opens new avenues for the development of targeted therapies aimed at preserving vascular integrity and cognitive function in individuals with diabetes. Moving forward, further investigation into the role of sEVs in diabetic complications may lead to innovative treatments to improve patient outcomes and quality of life.

Gustafson D, DiStefano PV, Wang XF, Wu R, Ghaffari S, Ching C, Rathnakumar K, Alibhai F, Syonov M, Fitzpatrick J, Boudreau E, Lau C, Galant N, Husain M, Li RK, Lee WL, Parekh RS, Monnier PP, Fish JE. (2024) Circulating small extracellular vesicles mediate vascular hyperpermeability in diabetes. Diabetologia [Epub ahead of print]. [article]

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