Lin Yao, Pang Qiongyi, Shi Yuanxi, Chen Xiang, Tu Fengxia
Department of Rehabilitation Medicine, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Neuroreport. 2025 May 7;36(7):350-363. doi: 10.1097/WNR.0000000000002157. Epub 2025 Apr 9.
The long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) might protect against cerebral ischemic injury. This study explored MALAT1's function in ischemic stroke and whether it acts through the caveolin-1/vascular endothelial growth factor (VEGF) pathway. A mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R) and a human brain microvascular endothelial cell (HBMEC) model of oxygen-glucose deprivation/reoxygenation (OGD/R) were established. Lentiviral vectors for MALAT1 knockdown, caveolin-1 knockdown, and MALAT1 overexpression were used for gene regulation studies. Neurological deficits, endothelial cell proliferation, cell apoptosis, cell viability, in vitro angiogenesis, cell migration, and the expression of related gene and protein were evaluated using the Zea Longa five-point scale, VEGF receptor 2/CD34 double immunofluorescence, TdT-mediated dUTP nick end labeling staining, cell counting kit-8 assay, tube formation assay, transwell assay, quantitative real time PCR, and western blot. In mouse MCAO/R model and HBMEC OGD/R model, the expression levels of MALAT1, caveolin-1, and VEGF were significantly upregulated compared to the control group. In vivo, downregulation of MALAT1 expression exacerbated cerebral ischemic injury as manifested by severe neurological deficits, larger infarct volume, increased apoptosis, decreased numbers of VEGF receptor 2+/CD34+ endothelial progenitor cells, increased cell apoptosis, and the downregulation of caveolin-1 and VEGF. Conversely, overexpression of MALAT1 partially reversed the inhibition of cell migration and tubule formation by caveolin-1 gene downregulation, and restored in the expression of caveolin-1 and VEGF. MALAT1 promotes angiogenesis after cerebral ischemic injury, likely in part via the caveolin-1/VEGF pathway. Thus, MALAT1 may serve as a potential therapeutic target for ischemic stroke.
长链非编码RNA转移相关肺腺癌转录本1（MALAT1）可能对脑缺血损伤具有保护作用。本研究探讨了MALAT1在缺血性卒中中的作用及其是否通过小窝蛋白-1/血管内皮生长因子（VEGF）途径发挥作用。建立了大脑中动脉闭塞/再灌注（MCAO/R）小鼠模型和氧糖剥夺/复氧（OGD/R）人脑微血管内皮细胞（HBMEC）模型。使用针对MALAT1敲低、小窝蛋白-1敲低和MALAT1过表达的慢病毒载体进行基因调控研究。采用Zea Longa五点量表、VEGF受体2/CD34双重免疫荧光、TdT介导的dUTP缺口末端标记染色、细胞计数试剂盒-8检测、管形成试验、Transwell试验、定量实时PCR和蛋白质印迹法评估神经功能缺损、内皮细胞增殖、细胞凋亡、细胞活力、体外血管生成、细胞迁移以及相关基因和蛋白质的表达。在小鼠MCAO/R模型和HBMEC OGD/R模型中，与对照组相比，MALAT1、小窝蛋白-1和VEGF的表达水平显著上调。在体内，MALAT1表达下调会加重脑缺血损伤，表现为严重的神经功能缺损、更大的梗死体积、细胞凋亡增加、VEGF受体2+/CD34+内皮祖细胞数量减少、细胞凋亡增加以及小窝蛋白-1和VEGF表达下调。相反，MALAT1过表达部分逆转了小窝蛋白-1基因下调对细胞迁移和小管形成的抑制作用，并恢复了小窝蛋白-1和VEGF的表达。MALAT1可能部分通过小窝蛋白-1/VEGF途径促进脑缺血损伤后的血管生成。因此，MALAT1可能成为缺血性卒中的潜在治疗靶点。
