Aging has been considered to be the most important non-modifiable risk factor for stroke and death. Changes in circulation factors in the systemic environment, cellular senescence and artery hypertension during human ageing have been investigated. Exosomes are nanosize membrane vesicles that can regulate target cell functions via delivering their carried bioactive molecules (e.g. protein, mRNA, and microRNAs). In the central nervous system, exosomes and exosomal microRNAs play a critical role in regulating neurovascular function, and are implicated in the initiation and progression of stroke. MicroRNAs are small non-coding RNAs that have been reported to play critical roles in various biological processes. Recently, evidence has shown that microRNAs are packaged into exosomes and can be secreted into the systemic and tissue environment. Circulating microRNAs participate in cellular senescence and contribute to age-associated stroke. Here, we provide an overview of current knowledge on exosomes and their carried microRNAs in the regulation of cellular and organismal ageing processes, demonstrating the potential role of exosomes and their carried microRNAs in age-associated stroke.

Introduction: Multicellular crosstalk within the brain tissue has been suggested to play a critical role in maintaining cerebral vascular homeostasis. Exosomes (EXs) mediated cell-cell communication, but its role in cerebral ischemic injury is largely unknown.Rab27a is one of the major genes controlling EX release. Here, we explored the role of Rab27a in regulating brain EXs secretion, and the effects of Rab27a-mediated EXs on ischemia evoked cerebral vascular disruption and brain injury.Methods: Cerebral ischemia was induced in Rab27a knockout (Rab27a −/− ) and wide type (WT) mice by transient middle cerebral artery occlusion (tMCAO). Differential gene expression analysis was performed in ischemic brain tissue by using mRNA sequencing. EXs isolated from brain tissue of Rab27a −/− and WT mice (EX WT or EX Rab27a−/− ) were pre-administrated into tMCAO operated Rab27a −/− mice or oxygen and glucose deprivation (OGD) treated primary brain vascular endothelial cells (ECs). Results:We demonstrated that Rab27a expression in the peri-infarct area of brain was significantly elevated, which was associated with local elevation in EXs secretion.Rab27a deficiency dramatically decreased the level of EXs in brain tissue of normal and tMCAO-treated mice, and Rab27a −/− mice displayed an increase in infarct volume and NDS, and a decrease in cMVD and CBF following tMCAO. Pre-infusion of EX WT increased the brain EXs levels in the tMCAO operated Rab27a −/− mice, accompanied with an increase in cMVD and CBF, and a decrease in infarct volume, NDS, ROS production, and apoptosis. The effects of EX Rab27a−/− infusion were much diminished although in a dose-dependent manner. In OGD-treated ECs, EX Rab27a−/− showed less effectivity than EX WT in decreasing ROS overproduction and apoptosis, paralleling with down-regulated expression of NOX2 and cleaved caspase-3.

BackgroundEndothelial microvesicles (EMVs) are closely associated with the status of endothelial cells (ECs). Our earlier study has shown that EMVs could exert protective roles in ECs by transferring their carried miR-125a-5p. However, whether circulating EMVs and their carried miR-125a-5p can be used as biomarkers in ischaemic stroke (IS) are remain unknown. Methods We recruited 72 subjects with IS, 60 subjects with high stroke risk and 56 age-matched controls. The circulating EMVs and their carried miR-125a-5p (EMV-miR-125a-5p) levels were detected. We used microRNA (miR) array to study expression changes of miRs in plasma EMVs samples of three IS patients and three matched healthy controls. Transient middle cerebral artery occlusion (tMCAO) was used to establish IS mouse model. Results EMVs level was obviously elevated in IS patients, with the highest level in acute stage, and was positively related to carotid plaque, carotid intima-media thickness (IMT), National Institutes of Health Stroke Scale (NIHSS), infarct volume. On the contrary, we observed that EMV-miR-125a-5p level was obviously reduced in IS, with the lowest level in acute stage, and was negatively correlated with carotid plaque, IMT, NIHSS scores, infarct volume. EMVs and EMV-miR-125a-5p levels were closely related with large artery atherosclerosis subgroup. Importantly, EMVs and EMV-miR-125a-5p levels could serve as independent risk factors, and receiver operating characteristic curve achieved an area under curve (AUC) of 0.720 and 0.832 for IS, respectively, and elevated to 0.881 after their combination. In IS mouse model, control EMVs or n-EMVs administration could decrease the infarct volume and neurological deficit score, while increase the cerebral blood flow of IS mice compared with vehicle group, while IS EMVs or oxygen and glucose deprivation (OGD)-EMVs administration aggravated the tMCAO induced ischaemic injury. In addition, we observed that OGD EMV miR-125a-5p could partially ameliorate the OGD EMVs induced brain injury after IS. Conclusions These findings demonstrate that circulating EMVs and EMV-miR-125a-5p are closely related with the occurrence, progress, subtypes and severity of IS, and they can serve as innovative biomarkers and therapeutic targets for IS, especially when they are combined. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE AND/OR POLICY⇒ This study will provide an innovative biomarkers and therapeutic targets for IS.