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Common and Distinct Circulating MicroRNAs Across Four Neurovascular Disorders

ABSTRACT: Background: Familial cerebral cavernous malformations (FCCM), Sturge-Weber Syndrome (SWS), and hereditary hemorrhagic telangiectasia with brain arteriovenous malformations (HHT) are neurovascular disorders driven by genetic mutations. Cerebral microbleeds (CMBs) are primarily associated with the aging process with less known about genetic drivers. This study hypothesizes that common and distinct circulating microribonucleic acids (miRNAs) reflect shared and different pathobiology and can serve as potential diagnostic and mechanistic biomarkers. Methods: Common and unique differentially expressed (DE) plasma miRNAs (p<0.05, FDR corrected, absolute fold change [|FC|]>1.5]) were identified between patients with FCCM, SWS, HHT and CMB, compared to age- and sex-propensity-matched healthy subjects. Ingenuity Pathway Analysis as well as transcriptome integration analyses were performed to identify gene targets and their associated pathways. Preselected miRNAs were finally validated using ddPCR. Results: Eleven DE miRNAs were identified in FCCM, 40 in SWS, 41 in HHT, and 26 in CMB (p<0.05, FDR-corrected, [|FC|]>1.5]). Further analyses showed that 18 DE miRNAs were commonly dysregulated in any two of the studied neurovascular disorders. The PI3K-Akt and ROBO SLIT signaling pathways were identified across all four disorders. The plasma levels of four of the 18 miRNAs were further validated (p<0.05) using ddPCR. Conclusion: The common dysregulated miRNAs across neurovascular disorders reflect shared pathophysiological pathways, underscoring their potential as biomarkers and therapeutic targets. These findings pave the way for further exploration of these miRNAs, aiming at the clinical application for disease monitoring and therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE287906 | GEO | 2025/08/07

REPOSITORIES: GEO

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Project description:Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominantly inherited vascular disease characterized by the presence of mucocutaneous telangiectasia and arteriovenous malformations in visceral organs. HHT is predominantly caused by mutations in ENG and ACVRL1, Which both belong to the TGF-M-NM-2 signalling pathway. Further knowledge on how a disturbance of the TGF-M-NM-2 signalling pathway leads to HHT manifestations is needed in order to identify potential therapeutic targets. As long non-coding RNAs (lncRNAs) are increasingly recognized as key regulators of gene expression and constitute a sizable fraction of the human transcriptome, we wanted to assess whether lncRNAs play a role in the molecular pathogenesis of HHT. Here we used microarray analysis to profile lncRNAs to compare the expression of HHT telangiectasial and HHT non-telangiectasial nasal tissue from the same patient in a paired design. The microarray probes were re-annotated using the GENCODE v.16 dataset, identifying 4,810 probes mapping to 2,811 lncRNAs. By comparing HHT telangiectasial tissue versus HHT non-telangiectasial tissue, we identified 42 lncRNAs that are differentially expressed (q<0.001). Using GREAT, a tool that assumes cis-regulation, we showed that differently expressed lncRNAs are enriched for genomic loci involved in key pathways concerning HHT. Our study identified lncRNAs that are aberrantly expressed in HHT telangiectasia and indicates that lncRNAs may contribute to regulate protein-coding loci in HHT. Which suggest that the lncRNA component of the transcriptome deserves more attention in HHT. A deeper understanding of lncRNAs and their role in telangiectasia formation possesses potential for discovering therapeutic targets in HHT. Gene expression profiling of 80 paired nasal samples from patients with hereditary Haemorrhagic Telangiectasia (HHT), representing telangiectasial and non-telangiectasial (normal) tissue respectively. The patients were divided into HHT1 or HHT2 in regard to the germline mutation in ENG (HHT1) or ACVRL1 (HHT2). Additional controls were healthy siblings (not carrying the germline mutation) and external controls. The study was conducted using Agilent-028004 SurePrint G3 Human GE 8x60K Microarray platform.

Project description:Hereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations focally develop in multiple organs. These can be small (telangiectasias) or large (arteriovenous malformations, AVMs) and can compromise tissue perfusion. Critically, they are prone to rupture leading to frequent and uncontrolled bleeding. As a result, HHT patients experience several debilitating clinical manifestations that reduce patient quality-of-life. Most HHT patients are heterozygous for loss-of-function mutations affecting signaling through the Alk1 pathway; yet, the pathogenesis of vascular malformation (VM) in HHT patients remains unclear and there are still few treatment options and no cure. Due to the complex, three-dimensional, and multicellular nature of vascular lesions in HHT, they are traditionally studied in intact genetically-modified mouse and zebrafish models, and studies in these animals have yielded important insights into HHT disease progression. However, intact animal studies can be time-consuming and expensive, and may be difficult to translate to human patients. In this study, we take advantage of our recently developed Vascularized Micro-Organ platform to develop an in vitro fully-humanized HHT-on-a-chip microphysiological model (HHT-VMO) that recapitulates vascular lesions of HHT patients. Using a tunable IPTG-inducible ACVRL1 (Alk1)-knockdown approach, we control the timing and extent of endogenous Alk1 expression in primary human endothelial cells seeded into the HHT-VMO device. We report that Alk1-deficient EC reliably form networks with aberrant morphology that includes lesions reminiscent of both patient telangiectasias and AVMs. HHT-VMO lesions are dependent upon the timing of Alk1 knockdown and their formation is blocked by the Vascular Endothelial Growth Factor Receptor (VEGFR) inhibitor pazopanib. Lastly, we find that AVM-like lesions that form in the HHT-VMO are comprised of mixed Alk1-intact and Alk1-deficient EC suggesting cell non-autonomous effects. Taken together, we report development of a novel HHT-on-a-chip model that appears to faithfully reproduce HHT patient lesions. In the future, we hope to use this model to better understand HHT disease biology and to perform drug screening studies to identify a cure for HHT.

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Common and Distinct Circulating MicroRNAs Across Four Neurovascular Disorders

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