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PO1-2-37

Role of Serum Exosomes in Regulating Endothelial Function in Diabetes

[Speaker] Yifan Wang:1
[Co-author] Huina Zhang:1, Jian Liu:1, Yu Huang:1
1:School of Biomedical Sciences, School of Biomedical Sciences and Institute of Vascular Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China

Background
Exosomes are found abundant in blood, and the various molecules contained in exosomes can be delivered to recipient cells via blood circulation, representing a novel route for cell-cell communication. Vascular endothelial cells are in direct and constant contact with circulating substances, including serum exosomes. Therefore, we aim to investigate how serum exosomes regulate endothelial functions and its role in diabetes-associated vascular complications.

Methods
To test vascular function, mouse aortas were dissected and isometric force was measured using wire myograph. To measure NO bioavailability, endothelial cells were stained with NO-sensitive fluorescent dye and NO production was detected by confocal microscopy. Expression of target genes were measured by RT-PCR and western blot.

Results
The present study shows vascular endothelial cell is able to take up PKH67-labeled serum exosomes isolated from diabetic (db/db) mouse indicated by increased incorporation of fluorescence into aortic endothelial cells. db/db serum exosomes reduced NO production in endothelial cells, and severely impaired NO-dependent vascular relaxation in non-diabetic (db/m+) mice conduit and resistant arteries. The impaired vascular function can be rescued by co-treatment with heparin (exosome uptake inhibitor) or eNOS substrate L-arginine. In addition, serum exosomes from db/db mouse and diabetic Zucker (fa/fa) rat induced proliferation in primary cultured mouse and rat endothelial cells. Screening of the expression of tight junction proteins showed significant downregulation of Cldn1 and upregulation of Zo2 in endothelial cells treated by serum exosomes from diabetic mouse or rat.

Conclusions
The present results suggested that serum exosomes inhibit NO production and impair endothelial function in mouse aorta. Serum exosomes also impair vascular integrity by altering the tight junction composition, which might contribute to diabetes-associated microvascular complications (supported by RGC-CRF and RGC-GRF).

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