Circulating microRNAs Associated With Reversible Cerebral Vasoconstriction Syndrome

Ann Neurol. 2021 Mar;89(3):459-473. doi: 10.1002/ana.25965. Epub 2020 Dec 30.


Objective: The purpose of this study was to investigate the significance of circulating micro RNAs (miRNAs) in the pathogenesis of reversible cerebral vasoconstriction syndrome (RCVS).

Methods: We prospectively recruited 3 independent cohorts of patients with RCVS and age-matched and sex-matched controls in a single medical center. Next-generation small RNA sequencing followed by quantitative polymerase chain reaction (PCR) was used to identify and validate differentially expressed miRNAs, which was cross-validated in migraine patients in ictal stage or interictal stage. Computational analysis was used to predict the target genes of miRNAs, followed by in vitro functional analysis.

Results: We identified a panel of miRNAs including miR-130a-3p, miR-130b-3p, let-7a-5p, let-7b-5p, and let-7f-5p that well differentiated patients with RCVS from controls (area under the receiver operating characteristics curve [AUC] was 0.906, 0.890, and 0.867 in the 3 cohorts, respectively). The abundance of let-7a-5p, let-7b-5p, and let-7f-5p, but not miR-130a-3p nor miR-130b-3p, was significantly higher in patients with ictal migraine compared with that of controls and patients with interictal migraine. Target prediction and pathway enrichment analysis suggested that the transforming growth factor-β signaling pathway and endothelin-1 responsible for vasomotor control might link these miRNAs to RCVS pathogenesis, which was confirmed in vitro by transfecting miRNAs mimics or incubating the patients' cerebrospinal fluid (CSF) in 3 different vascular endothelial cells. Moreover, miR-130a-3p was associated with imaging-proven disruption of the blood-brain barrier (BBB) in patients with RCVS and its overexpression led to reduced transendothelial electrical resistance (ie, increased permeability) in in vitro human BBB model.

Interpretation: We identified the circulating miRNA signatures associated with RCVS, which may be functionally linked to its headache, BBB integrity, and vasomotor function. ANN NEUROL 2021;89:459-473.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Blood-Brain Barrier / physiopathology*
  • Capillary Permeability
  • Case-Control Studies
  • Cerebrovascular Disorders / blood
  • Cerebrovascular Disorders / genetics*
  • Cerebrovascular Disorders / physiopathology
  • Circulating MicroRNA / blood*
  • Circulating MicroRNA / genetics
  • Computer Simulation
  • Electric Impedance
  • Endothelial Cells*
  • Endothelin-1 / genetics
  • Endothelin-1 / metabolism
  • Female
  • High-Throughput Nucleotide Sequencing
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • In Vitro Techniques
  • Male
  • MicroRNAs / blood*
  • Middle Aged
  • Migraine Disorders / blood
  • Migraine Disorders / genetics
  • Migraine Disorders / physiopathology
  • Reproducibility of Results
  • Sequence Analysis, RNA
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Vasoconstriction / genetics*
  • Vasomotor System / physiopathology


  • Circulating MicroRNA
  • Endothelin-1
  • MIRN130 microRNA, human
  • MicroRNAs
  • Transforming Growth Factor beta
  • mirnlet7 microRNA, human