Department of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Pharmacology and Toxicology, Wright State University Boonshoft School of Medicine, Dayton, Ohio, USA.
Stroke Vasc Neurol. 2023 Apr;8(2):89-102. doi: 10.1136/svn-2021-001476. Epub 2022 Sep 15.
Endothelial 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.
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.
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 could partially ameliorate the OGD EMVs induced brain injury after IS.
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.
内皮细胞来源的微小囊泡（EMVs）与内皮细胞（ECs）的状态密切相关。我们之前的研究表明，EMVs 可以通过转移其携带的 miR-125a-5p 发挥对 ECs 的保护作用。然而，循环 EMVs 及其携带的 miR-125a-5p 是否可作为缺血性中风（IS）的生物标志物尚不清楚。
我们招募了 72 例 IS 患者、60 例高中风风险患者和 56 名年龄匹配的对照者。检测循环 EMVs 及其携带的 miR-125a-5p（EMV-miR-125a-5p）水平。我们使用 microRNA（miR）阵列研究了 3 例 IS 患者和 3 例匹配的健康对照者血浆 EMVs 样本中 miR 的表达变化。采用短暂性大脑中动脉闭塞（tMCAO）建立 IS 小鼠模型。
IS 患者的 EMVs 水平明显升高，急性期最高，并与颈动脉斑块、颈动脉内膜中层厚度（IMT）、美国国立卫生研究院卒中量表（NIHSS）评分、梗死体积呈正相关。相反，我们发现 IS 患者的 EMV-miR-125a-5p 水平明显降低，急性期最低，与颈动脉斑块、IMT、NIHSS 评分、梗死体积呈负相关。EMVs 和 EMV-miR-125a-5p 水平与大动脉粥样硬化亚组密切相关。重要的是，EMVs 和 EMV-miR-125a-5p 水平可作为独立的危险因素，受试者工作特征曲线（ROC）的曲线下面积（AUC）分别为 0.720 和 0.832，联合后可提高至 0.881。在 IS 小鼠模型中，与载体组相比，对照 EMVs 或 n-EMVs 给药可降低 IS 小鼠的梗死体积和神经功能缺损评分，增加脑血流量，而 IS EMVs 或氧葡萄糖剥夺（OGD）-EMVs 给药加重 tMCAO 诱导的缺血性损伤。此外，我们发现 OGD EMV 可部分改善 IS 后 OGD EMV 诱导的脑损伤。
这些发现表明，循环 EMVs 和 EMV-miR-125a-5p 与 IS 的发生、进展、亚型和严重程度密切相关，可作为 IS 的创新生物标志物和治疗靶点，尤其是联合使用时。
