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Moyamoya disease (MMD) is a chronic cerebrovascular disorder and a leading cause of pediatric stroke. Extracellular vesicles (EVs) carrying microRNAs (miRNAs) play a pivotal role in intercellular communication within cerebrovascular diseases. This study aimed to identify specific miRNAs within plasma-derived EVs from MMD patients and investigate their functional implications. Study subjects included healthy controls ( N  = 13) and MMD patients ( N  = 23). EVs were isolated from plasma samples and characterized by transmission electron microscopy, nanoparticle tracking analysis, ExoView, RT-qPCR, and immunoblotting. miRNA profiles were assessed through NanoString analysis. Functional effects of miR-512-3p inhibition were evaluated in MMD endothelial colony-forming cells (ECFCs) by analyzing guanosine triphosphatase (GTPase) activity, tubule formation, and cell viability. MMD-derived EVs exhibited an upregulation of miR-512-3p compared to controls. Bioinformatics analysis identified RHO guanine nucleotide exchange factor 3 (ARHGEF3) as a potential target of miR-512-3p. Inhibition of miR-512-3p in MMD ECFCs resulted in increased expression of ARHGEF3 and its downstream effector RHOA, leading to enhanced GTPase activity and improved tubule formation, indicative of restored angiogenic function. Elevated levels of miR-512-3p within plasma-derived EVs may serve as a novel biomarker for MMD diagnosis. The modulation of ARHGEF3 and subsequent RHOA signaling by targeting miR-512-3p contributes to the dysregulated angiogenesis in MMD.

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive stenosis of large intracranial arteries and formation of fragile collateral vessels that can be triggered by a broad range of genetic and immune factors. Central to MMD pathology is excessive proliferation of vascular smooth muscle cells (VSMCs) in the intima of affected arteries associated with contractile-to-synthetic phenotypic switching, but the underlying molecular mechanisms remain unclear. To identify dysregulated pathways we studied a cohort of 12 patients with well-documented MMD, including one post-mortem autopsy case, using a multi-omics approach combining whole exome sequencing with plasma proteomics. In addition, we conducted an in-depth spatial proteomics analysis of an occluded artery retrieved post-mortem from one idiopathic patient, combining targeted antibody-based imaging with laser capture microdissection coupled to mass spectrometry. Genetic predispositions for MMD was found in 8 out of 12 patients (67%), including three patients with variants in the major susceptibility gene RNF213 and five with varying underlying genetic conditions (trisomy 21, pathogenic variants in ACTA2 , SAMHD1 , NFIA ). Artery spatial proteomics revealed phenotypic switching of vascular smooth muscle cells associated with infiltration of these cells in the intima, including loss of contractile and gain of synthetic marker proteins. Most notably, increased expression of cellular fibronectin in the occluded lesion was associated with increased levels in patients’ plasma, providing a rationale for cellular fibronectin as potential tissue leakage biomarker for moyamoya disease. Finally, infiltration of macrophages and antigen-presenting cells in the intima pointed to a role for inflammatory signals in disease progression. Together, our data provide an unprecedented spatial view on protein changes in an occluded moyamoya artery, revealing intimal infiltration of synthetic vascular smooth muscle cells and antigen-presenting immune cells as key pathological findings, opening novel avenues for future diagnosis and research.

The ring finger protein 213 (RNF213) Arg4810Lys variant has been previously identified as a significant risk factor for Moyamoya disease (MMD), particularly in East Asian populations. This review explores the broader impact of the Arg4810Lys mutation on various cerebrovascular conditions, including Moyamoya syndrome (MMS), intracranial artery stenosis, quasi-Moyamoya syndromes, ischemic stroke, and intracranial atherosclerosis. Beyond the brain, it is also implicated in pulmonary arterial hypertension, coronary artery disease, and renal artery stenosis, emphasizing its systemic effects. Functional studies suggest that RNF213 Arg4810Lys alters angiogenic signaling, endothelial cell function, vascular remodeling, and immune response pathways, especially when influenced by environmental stressors, like hypoxia or inflammation. The gene dosage of Arg4810Lys significantly affects disease phenotypes, with homozygous carriers typically experiencing earlier onset with increased severe symptoms. The variant also exhibits incomplete penetrance and frequently co-occurs with additional genetic alterations, including trisomy, KIF1A, FLNA, and PCSK9 mutations, which complicates its pathogenicity. A comprehensive understanding of RNF213 Arg4810Lys’s systemic impact is essential to developing effective risk assessment strategies, personalized treatments, and targeted therapies for associated vascular diseases.

Moyamoya disease (MMD) is a rare occlusive cerebrovascular disease, and its pathological mechanism remains unclear at present. The abnormal vascular remodeling may be involved in vascular endothelial cells. In this study, RNA seq was performed on the superficial temporal arteries of 10 patients with MMD. Integrated analysis was conducted by combining validation set with training set. Key genes were identified through differential analysis and WGCNA. The functions of potential biomarkers were explored by methods such as correlation analysis, KEGG analysis, PPI network, and tube formation experiments. Integrated analysis of three cohorts (43 MMD vs. 26 controls) identified 19 shared DEGs, including upregulated KRT8/KRT18 and downregulated NT5C2 ( P  < 0.001). Enrichment revealed dysregulation in circadian rhythm, calcium signaling, and metabolic pathways ( P  < 0.05). Immune infiltration showed elevated pro-inflammatory cells (neutrophils, M1 macrophages) and reduced Tregs/NK cells ( P  < 0.05). Machine learning (SVM-RFE, Boruta, LASSO) prioritized KRT8 as diagnostic markers (AUC > 0.96). KRT8 overexpression enhanced angiogenesis in HBMECs (1.5-fold tube formation, P  < 0.01). This omics approach delineates MMD’s molecular interplay between inflammation, metabolism, and vascular remodeling. KRT8 may promote vascular remodeling in MMD by regulating the tube-forming ability of endothelial cells. This could be a highlight of therapeutic targets for MMD and shed light on the mechanism research of MMD.

The pathogenesis and development of Moyamoya disease are still unclear. This study aimed to investigate the effect of desmoglein-2 (DSG2) on Moyamoya disease and determine the inhibitory effect of DSG2 in vascular remodeling in Moyamoya disease. RNA sequencing, immunohistochemistry (IHC), and western blotting were used to detect the expression of DSG2 in the superficial temporal artery (STA) tissues of Moyamoya disease. The association between DSG2 and endothelial cells’ biological activities was investigated by cell counting kit-8 (CCK-8), migration assay, tube formation assay, flow cytometry with Annexin V-FITC/PI staining, and TUNEL apoptotic cell detection kit. Pathways affected by overexpression or knockdown of DSG2 were identified in endothelial cells. The expression of DSG2 in the STA tissues of Moyamoya disease was lower than that in normal controls. Overexpression of DSG2 inhibits the proliferation and migration but promotes apoptosis in endothelial cells, and low DSG2 levels result in impaired angiogenesis. In addition, there was an interaction between DSG2 and MMP-9, and DSG2 acted through the PI3K signaling in endothelial cells. Our results indicate that DSG2 affects PI3K signaling in vascular endothelial cells, and MMP-9 is involved in DSG2-mediated vascular changes in Moyamoya disease.

Cognitive dysfunction is a common symptom in moyamoya disease (MMD). However, the mechanisms underlying this impairment, particularly the changes in serum metabolites, have not been thoroughly investigated. The primary objective of this study was to utilize untargeted metabolomics technology to analyze serum metabolic profiles in MMD patients and to explore the potential relationship between metabolic alterations and cognitive function. Thirty patients with MMD and ten healthy controls were enrolled in our study. Cognitive assessment composing Montreal Cognitive Assessment (MoCA) and Hopkins Verbal Learning Test-Revised (HVLT-R) were used in this study to appraise general cognition and specific cognitive domains, including immediate recall, delayed recall, and delayed recognition. Serum samples were collected for metabolomics analysis that through using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify and identify metabolomics. Differentially expressed metabolites were identified based on fold changes and statistical significance. Additionally, correlation analyses were performed to evaluate the associations between identified differential metabolites and cognitive function. Our results found that overall cognitive function and the subdomains of cognitive function include immediate memory, delayed recall, and recognition in MMD patients were significantly impaired. The untargeted metabolomics analysis identified 142 significantly altered metabolites in the serum of MMD patients compared to controls. Of these, 22 metabolites were downregulated, while 120 metabolites were upregulated. We identified significant alterations in bile acid, amino acid, peptide, and purine metabolism, along with changes in lipid metabolism, inflammation, hormonal regulation, and protein metabolism in the MMD group, suggesting a complex metabolic dysregulation in MMD. Furthermore, correlation analysis indicated that the metabolomic changes in MMD patients were strongly associated with cognitive dysfunction, implying their potential involvement in the pathophysiology of cognitive impairment. In conclusion, our study provides evidence that cognitive dysfunction in MMD are associated with significant metabolic changes. The altered serum metabolites highlight the needs to comprehensively understand and manage cognitive dysfunction in MMD patients.

Background Moyamoya disease (MMD) is a chronic, progressive occlusive cerebrovascular disease. It causes recurrent cerebrovascular stroke due to vascular closure and proliferation. An unclear pathophysiological mechanism is the most significant obstacle in the diagnosis and treatment of MMD. Method This study prospectively included 10 MMD and 3 HC (healthy controls) participants in the discovery cohort. GSE189993 and GSE157628 were downloaded from the Gene Expression Omnibus (GEO) as validation cohorts, which included 32 patients with MMD and 20 HC. Angiogenesis-related genes were downloaded from GENECARD. Hub genes were selected by differential analysis and weighted correlation network analysis. Functional enrichment, immune infiltration, and metabolic pathway analyses and drug prediction mapping (Connectivity Map [CMap]) were performed. Result Through differential analysis identified, 198 differentially expressed genes (DEGs), including 85 upregulated genes and 113 downregulated genes. In total, 238 angiogenesis -related genes were identified using WGCNA. Four hub genes were identified: TBC1 domain family member 9B (TBC1D9B), Phosphatidylinositol transfer protein beta (PITPNB), The ANK repeat and PH domain-containing protein 3 (ARAP3), and Ubiquitin-conjugating enzyme E2 E1 (UBE2E1). Four potential drugs were selected: calyculin A, H-9, parbendazole, and velnacrine. The results of multiple immune infiltration analyses collectively depicted the immune microenvironment characteristics of MMD. Conclusion This study is the first to explore the mechanism by which angiogenesis related genes are involved in intimal hyperplasia in Moyamoya disease. TBC1D9B and ARAP3 may promote the pathological development of moyamoya disease through immune response, metabolism.

Moyamoya disease is an idiopathic human cerebrovascular disorder that is characterized by progressive stenosis and abnormal collateral vessels. We recently identified mysterin/RNF213 as its first susceptibility gene, which encodes a 591-kDa protein containing enzymatically active P-loop ATPase and ubiquitin ligase domains and is involved in proper vascular development in zebrafish. Here we demonstrate that mysterin further contains two tandem AAA+ ATPase modules and forms huge ring-shaped oligomeric complex. AAA+ ATPases are known to generally mediate various biophysical and mechanical processes with the characteristic ring-shaped structure. Fluorescence correlation spectroscopy and biochemical evaluation suggested that mysterin dynamically changes its oligomeric forms through ATP/ADP binding and hydrolysis cycles. Thus, the moyamoya disease-associated gene product is a unique protein that functions as ubiquitin ligase and AAA+ ATPase, which possibly contributes to vascular development through mechanical processes in the cell.

Immuno-inflammation has been shown to play a pivotal role in the pathogenesis of moyamoya disease (MMD). However, how did circulating Treg/Th17 cells involve in MMD patients remains unclear. 26 MMD, 21 atherothrombotic stroke, and 32 healthy controls were enrolled in this study. MMD patients have a significantly higher percentage of circulating Treg and Th17 cells as well as their dominantly secreting cytokines than other groups ( P  < 0.0001), whereas no difference was found in the ratio of Treg/Th17 between patients in MMD and atherothrombotic stroke group or control subjects ( P  = 0.244). However, the increased Treg in MMD patients which were enriched with FrIII Treg cells had deficient suppressive functions ( P  = 0.0017) compared to healthy volunteers. There was a positive correlation between Treg or TGF-β and MMD Suzuki’s stage. And the level of circulating Treg was as an independent factor associated with MMD stage. Besides, TGF-β was also correlated with the increased expression of VEGF in MMD patients. Our findings indicated an important involvement of circulating Treg in the pathogenic development of MMD and TGF-β in Treg induced VEGF.

Moyamoya disease (MMD) is a rare chronic progressive vascular anomaly of the skull base whose molecular regulatory mechanisms remain poorly understood. We therefore aimed to analyze the molecular mechanisms involved in the development of MMD from the perspective of miRNA regulation of mRNA. Raw gene expression profiles (GSE178501, GSE157628 and GSE189993) were downloaded from the Gene Expression Omnibus database and used to identify differentially expressed genes and perform functional enrichment analysis. Differentially expressed miRNAs and their predicted target genes were validated by RT-qPCR. Oxygen glucose deprivation was applied to induce an inflammatory injury cell model in human brain microvascular endothelial cells (BMEC). 973 differentially expressed mRNAs and 3 differentially expressed miRNAs were identified in three sets of gene expression profiles. RT-qPCR confirmed that the miR-29b-3p was upregulated in leukocytes of MMD and that the expression of NTRK2 was downregulated. Dual-luciferase reporter assay indicated that NTRK2 was the direct target of miR-29b-3p . Overexpression of NTRK2 improved the viability of BMEC and increased the protein levels of NTRK2 and pPI3K, while suppressed the expression of NLRP3, IL1β, and TNF-α. miR-29b-3p treatment partially abolished the protective effect of NTRK2 and diminished the effect of NTRK2 on PI3K/NLRP3 pathway. In conclusion, this study provided a novel insight into the pathophysiological mechanisms of MMD and demonstrated that the miR-29b-3p / NTRK2 /PI3K/NLRP3 axis plays a pivotal role in the progression of MMD.