Objective: Cerebral cavernous malformations (CCMs) are clinically significant because they can result in hemorrhagic strokes and seizures. Mutations that cause functional loss in the Ccm complex and somatic mutations in the PIK3CA gene are essential factors leading to the formation of CCMs. MicroRNAs regulate the brain vascular integrity and are implicated in the development of CCMs. This study aims to investigate the role of microRNA-21-3p in cerebral hemorrhage associated with CCMs and to explore the potential mechanisms to identify a novel therapeutic target. Methods: The expression of miR-21-3p and its direct target genes of NADPH oxidase (NOX4) and vascular endothelial growth factor A (VEGFA) in endothelial cells and pericytes was assessed in cavernous malformation lesions of 20 sporadic CCM patients by fluorescence in situ hybridization. The association of their expression with hemorrhage manifestation was evaluated. Cell proliferation, permeability, reactive oxygen species (ROS), migration, tubule formation, and the expression of NOX4 and VEGFA were assessed in CCM2 gene-depleted human brain microvascular endothelial cells (BMECs) and pericytes after miR-21-3p intervention. Cerebral hemorrhage, vascular permeability, vascular dilation, and angiogenesis after miR-21-3p intervention were evaluated in the ccm2 gene-knockdown zebrafish. Results: MiR-21-3p and CCM2 mRNA levels were significantly reduced in CCM lesions compared to normal brain tissue. Decreased miR-21-3p and increased NOX4 and VEGFA expression were shown in endothelial cells and pericytes of the CCM lesions compared to peri-lesion normal vessels from temporal lobe epilepsy patients, which were also correlated with the presence of cerebral hemorrhage in CCM patients. The in vitro CCM2 gene-depleted BMEC and pericyte studies showed that increasing miR-21-3p intervention attenuated BMEC and pericyte proliferation, permeability, ROS expression, endothelial cell migration, and tubule formation by targeting NOX4 and VEGFA. In vivo studies revealed that increasing miR-21-3p reduced cerebral hemorrhage, vascular permeability, vascular dilation, and angiogenesis in ccm2 gene-knockdown zebrafish. The expression levels of nox4 and vegfa in the zebrafish brain increased after ccm2 knockdown but were inhibited by miR-21-3p mimic. Conclusion: MiR-21-3p can be a novel therapeutic target by regulating NOX4 and VEGFA, thereby stabilizing vascular integrity and reducing cerebral hemorrhage in CCM lesions.
Guo et al. (Thu,) studied this question.
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