Long noncoding RNA MALAT1 promotes angiogenesis through the caveolin-1/VEGF pathway after cerebral ischemic injury.

Abstract

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.