Circulating microRNAs Associated With Reversible Cerebral Vasoconstriction Syndrome

Abstract

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

Non-coding RNAs in the regulation of blood–brain barrier functions in central nervous system disorders

“…In tuberous sclerosis complex (TSC), high protein expression of MMPs (MMP2, 3, 9, and 14) and TIMPs (endogenous tissue inhibitors 1, 2, 3, and 4) in TSC tubers was associated with BBB dysfunction, while these dysregulated proteins can be partly rescued by miR-146a and miR-147b in tuber-derived TSC cultures [ 204 ]. In reversible cerebral vasoconstriction syndrome (RCVS), high expression of circulating miR-130a-3p was associated with BBB disruption in patients, and overexpression of miR-130a-3p also led to increased BBB permeability in vitro [ 205 ]. Neuropilin-1 (Npn-1) has been suggested to play a critical role in regulating endothelial barrier dysfunction in response to VEGF [ 206 ] or interferon-γ [ 207 ], and Mone et al demonstrated that Npn-1 is a direct target of miR-24, which could negatively regulate Npn-1 mediated endothelial permeability [ 208 ].…”

Plasma MicroRNA Signature Panel Predicts the Immune Response After Antiretroviral Therapy in HIV-Infected Patients

“…Circulating miRNAs have essential roles in the diagnosis, prognosis, and evaluation of the therapeutic efficacy of different diseases ( 61 , 62 ). During HIV-1 infection, the miRNA profile of the host changes, and miRNA expression varies with disease progression ( 40 ).…”

Breakthroughs on the clinical management of headache and questions that need to be solved

“…68 One thing of note, an investigation was performed at the molecular level, which found that the abundance of 5miR-NAs (let-7a-5p, let-7b-5p, let-7f-5p, miR-130a-3p, and miR-130b-3p) changed in ictal-stage of migraine by TGF-β signaling pathway and reposed to endothelin-1, indicating that miRNA may play a role in reversible cerebral vasoconstriction syndrome (RCVS) pathogenesis. 69 However, our understanding of the mechanic of headaches is still limited, we need much more further studies through basic clinical trials and animal models.…”