Endothelial cell derived microvesicles modulate cerebrovascular and brain aging via miR-17-5p and serve as potential biomarkers for vascular aging

Vascular aging, characterized by brain endothelial cells (ECs) senescence and dysfunction, has been known to lead to various age-related cerebrovascular and neurodegenerative diseases. However, its underlying mechanisms remain elusive. ECs derived microvesicles (EMVs) and exosomes (EEXs) carry the characteristics of parent cells and transfer their contents to modulate the functions of recipient cells, holding the potential to evaluate or regulate vascular aging. Here, we found that young or aged ECs released EMVs were more effective than their released EEXs on alleviating or aggravating mice cerebrovascular and brain aging as indicated by SA-β-gal staining, cerebral blood flow, blood brain barrier function, aging related markers and cognitive ability test. We further identified that these EMVs regulated cerebrovascular and brain aging by transferring miR-17-5p and could modulate ECs senescence and functions via miR-17-5p/PI3K/Akt pathway. Plasma EMVs and their contained miR-17-5p (EMV-miR-17-5p) were significantly increased or decreased in the elderly, and were closely correlated with vascular aging. Receiver Operating Characteristic (ROC) analysis showed that the area under the curve was 0.724 for EMVs, 0.77 for EMV-miR-17-5p and 0.815 for their combination for distinguishing vascular aging. Our results revealed the novel roles for EMVs that could more effectively modulate vascular and brain aging than EEXs by regulating ECs functions through miR-17-5p/PI3K/Akt pathway, and also suggested that EMVs and EMV-miR-17-5p represent promising biomarkers and therapeutic targets for vascular aging. ### Competing Interest Statement The authors have declared no competing interest. * ECs : endothelial cells EMVs : endothelial microvesicles EEXs : endothelial exosomes HUVECs : human umbilical vein endothelial cells BMECs : brain microvascular endothelial cells SA-β-gal : senescence-associated β-galactosidase CBF : cerebral blood flow BBB : blood brain barrier GSSG : oxidized glutathione MDA : malondialdehyde TERT : telomerase reverse transcriptase cMVD : cerebral microvascular density IMT : intima-media thickness DHE : Dihydroethidium MTT : 3-[[4][1],5-dimethylthiazyol-2-yl] -2,5-diphenyltetrazolium bromide qRT-PCR : quantitative reverse transcription PCR FBS : Fetal bovine serum EGM-2 : endothelial cell growth medium-2 IPA : Ingenuity Pathway Analysis [1]: #ref-4