Diagnostic Utility and Pathogenic Implication of Circulating MicroRNAs in Reversible Cerebral Vasoconstriction Syndrome

ABSTRACT: The pathophysiology of reversible cerebral vasoconstriction syndrome (RCVS) is elusive. We speculated that circulating miRNAs might participate in the pathogenesis of RCVS and could assist clinical diagnosis. We prospectively recruited 75 RCVS patients (including 20 in discovery cohort, 23 in validation cohort-1, and 32 in the validation cohort-2) together with 76 age- and sex-matched controls. Five miRNAs including miR-130a-3p, miR-130b-3p, let-7a-5p, let-7b-5p andlet-7f-5p were significantly upregulated in patients with RCVS during ictal stage in comparison with that in their remission stage or controls. The combined miRNA panel well differentiated patients from controls (area under curve of Receiver Operating Characteristic curve was 0.906, 0.890 and 0.867 in three different cohorts respectively.) The expression of miR-130a-3p was associated with disruption of blood-brain barrier. Target prediction and pathway enrichment analysis suggested that endothelin-1 (EDN1) and transforming growth factor-beta (TGF-β) signaling pathway might link these miRNAs to the pathogenesis of RCVS. In vitro functional validation in human umbilical vein endothelial cells (HUVEC), human blood-brain barrier cell line (hCMEC/D3 cells) and HEK 293 cells confirmed that EDN1 and genes (BMPR2, SMAD5 and TGFBR2) involved in TGF-β signaling pathway were downregulated by these miRNAs. These miRNAs were correlated with plasma endothelin-1 level in the controls but not patients, indicating a deregulated feedback loop in patients during the disease state. To conclude, we identified the miRNA signatures associated with RCVS, which revealed excellent diagnostic performance, clinical relevance, and were functionally relevant to the putative pathomechanisms.

ORGANISM(S): Homo sapiens

PROVIDER: GSE145581 | GEO | 2023/02/19

REPOSITORIES: GEO