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ResearchIn-Press PreviewCardiologyVascular biology Open Access | 10.1172/JCI180900

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

Aida Collado,1 Rawan Humoud,1 Eftychia Kontidou,1 Maria Eldh,2 Jasmin Swaich,1 Allan Zhao,3 Jiangning Yang,1 Tong Jiao,1 Elena Domingo,4 Emelie Carlestål,5 Ali Mahdi,1 John Tengbom,1 Ákos Végvári,6 Qiaolin Deng,3 Michael Alvarsson,5 Susanne Gabrielsson,2 Per Eriksson,1 Zhichao Zhou,1 and John Pernow1

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Collado, A. in: JCI | PubMed | Google Scholar |

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Humoud, R. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Kontidou, E. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Eldh, M. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Swaich, J. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Zhao, A. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Yang, J. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Jiao, T. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Domingo, E. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Carlestål, E. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Mahdi, A. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Tengbom, J. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Végvári, Á. in: JCI | PubMed | Google Scholar |

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Deng, Q. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Alvarsson, M. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Gabrielsson, S. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Eriksson, P. in: JCI | PubMed | Google Scholar |

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Zhou, Z. in: JCI | PubMed | Google Scholar

1Division of Cardiology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

2Division of Immunology and Respiratory Medicine, Department of Medicine Sol, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

3Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

4Department of Pharmacology, Faculty of Medicine and Odontology, University of Valencia, Valencia, Spain

5Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

6Division of Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

Find articles by Pernow, J. in: JCI | PubMed | Google Scholar

Published March 20, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI180900.
Copyright © 2025, Collado et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published March 20, 2025 - Version history
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Abstract

Red blood cells (RBCs) induce endothelial dysfunction in type 2 diabetes (T2D), but the mechanism by which RBCs communicate with the vessel is unknown. This study tested the hypothesis that extracellular vesicles (EVs) secreted by RBCs act as mediators of endothelial dysfunction in T2D. Despite a lower production of EVs derived from RBCs of T2D patients (T2D RBC-EVs), their uptake by endothelial cells was greater than that of EVs derived from RBCs of healthy individuals (H RBC-EVs). T2D RBC-EVs impaired endothelium-dependent relaxation and this effect was attenuated following inhibition of arginase in EVs. Inhibition of vascular arginase or oxidative stress also attenuated endothelial dysfunction induced by T2D RBC-EVs. Arginase-1 was detected in RBC-derived EVs, and arginase-1 and oxidative stress were increased in endothelial cells following co-incubation with T2D RBC-EVs. T2D RBC-EVs also increased arginase-1 protein in endothelial cells following mRNA silencing and in the endothelium of aortas from endothelial cell arginase 1 knockout mice. It is concluded that T2D-RBCs induce endothelial dysfunction through increased uptake of EVs that transfer arginase-1 from RBCs to the endothelium to induce oxidative stress and endothelial dysfunction. These results shed important light on the mechanism underlying endothelial injury mediated by RBCs in T2D.

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  • Version 1 (March 20, 2025): In-Press Preview
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