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Extracellular vesicles from early- and late-passage endothelial cells differentially regulate cerebrovascular and brain aging in mice via changes in a miR-17-5p-dependent pathway

ABSTRACT: Vascular aging, which is characterized by brain endothelial cell (EC) senescence and dysfunction, is known to contribute to various age-related cerebrovascular and neurodegenerative diseases. However, the underlying mechanisms remain unclear. EC-derived microvesicles (EMVs) and exosomes (EEXs) retain the characteristics of parent cells and transfer their contents to modulate the functions of recipient cells, showing potential for evaluation or regulation of vascular aging. Here, as indicated by analyses of senescence-associated beta-galactosidase (SA-β-gal) staining, cerebral blood flow, blood–brain barrier function, aging-related markers and cognitive ability, we found that young primary EC (passage 2-4) released EMVs alleviated mouse cerebrovascular and brain aging more effectively than EEXs. Aged EC (passage 15-16) released EMVs were more effective than their released EEXs at exacerbating mouse cerebrovascular and brain aging. We further revealed that these EMVs regulated cerebrovascular and brain aging by transferring miR-17-5p and modulated EC senescence and function via the miR-17-5p/PI3K/Akt pathway. Clinically, the levels of plasma EMVs and their associated miR-17-5p (EMV-miR-17-5p) were significantly increased or decreased in elderly individuals and were closely correlated with reactive oxygen species (ROS) and vascular aging. Receiver operating characteristic (ROC) analysis revealed that the area under the curve (AUC) was 0.724 for EMVs, 0.77 for EMV-miR-17-5p and 0.815 for their combination for distinguishing vascular aging. Our results identified novel roles for EMVs and showed that these vesicles more effectively modulated vascular and brain aging than did EEXs by regulating EC functions through the miR-17-5p/PI3K/Akt pathway; thus, EMVs and EMV-miR-17-5p are promising biomarkers and therapeutic targets for vascular aging.

ORGANISM(S): Mus musculus

PROVIDER: GSE266940 | GEO | 2024/05/12

REPOSITORIES: GEO

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Project description:Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.Physical exercise stimulates adult hippocampal neurogenesis in mammals, and is considered a relevant strategy for preventing age-related cognitive decline in aging humans. However, its mechanism is controversial. Here, by investigating microRNAs (miRNAs) and their downstream pathways, we uncover that downregulation of miR-135a-5p mediates exercise-induced proliferation of adult NPCs in adult neurogenesis in the mouse hippocampus, likely by activation of phosphatidylinositol (IP3) signaling. Specifically, while overexpression of miR-135 prevents exercise-induced proliferation in the adult mouse hippocampus in vivo and in NPCs in vitro, its inhibition activates NPCs proliferation in resting and aged mice. Label free proteomics and bioinformatics analysis identifies 11 potential targets of miR-135 in NPCs, several of them involved in phosphatidylinositol signaling. Thus, miR-135a is key in mediating exercise-induced adult neurogenesis and opens intriguing perspectives toward the therapeutic exploitation of miR-135 to delay or prevent pathological brain ageing.

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Extracellular vesicles from early- and late-passage endothelial cells differentially regulate cerebrovascular and brain aging in mice via changes in a miR-17-5p-dependent pathway

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