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Background: Moyamoya disease (MMD) is characterized by an abundance of moyamoya vessels; however, the precise mechanism driving the spontaneous angiogenesis of these compensatory vessels remains unclear. Previous research has established a link between the stromal cell-derived factor-1 (SDF-1)/ CXC receptor 4 (CXCR4) axis and angiogenesis under hypoxic conditions. Nevertheless, the alterations in this axis within the cerebrospinal fluid, arachnoid membranes and vascular tissue of MMD patients have not been fully investigated., Methods: Our study enrolled 66 adult MMD patients and 61 patients with atherosclerotic vascular disease (ACVD). We investigated the SDF-1 concentration in cerebrospinal fluid (CSF) and CXCR4 expression level on the arachnoid membranes and vascular tissue. We utilized enzyme-linked immunosorbent assay and immunohistochemistr. Additionally, we cultured and stimulated human brain microvascular endothelial cells (HBMECs) and smooth muscle cells (SMCs) under oxygen and glucose deprivation (OGD) conditions followed by reoxygenation, to examine any changes in the SDF-1/CXCR4 axis., Results: The results demonstrated an elevation in the level of SDF-1 in CSF among MMD patients compared to those with ACVD. Moreover, the expression of CXCR4 in arachnoid membranes and vascular tissue showed a similar trend. Furthermore, the content of CXCR4 in HBMECs and SMCs increased with the duration of ischemia and hypoxia. However, it was observed that the expression of CXCR4 decreased at OGD/R 24h compared to OGD 24h. The temporal pattern of SDF-1 expression in HBMECs and SMCs mirrored that of CXCR4 expression., Conclusion: These findings indicate a critical role for the SDF-1/CXCR4 axis in the angiogenesis of moyamoya disease., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Moyamoya disease (MMD) is an occlusive cerebrovascular disease, causing stroke in children and young adults with unknown etiology. The fundamental pathology is fibrocellular intimal thickening of cerebral arteries, in which vascular smooth muscle cells (VSMCs) are observed as one of the major cell types. Although the characteristics of circulating smooth muscle progenitor cells have been previously reported, the VSMCs are poorly characterized in MMD. We aimed to characterize VSMCs in MMD using induced pluripotent stem cell (iPSC)-technology., Methods: We differentiated VSMCs from neural crest stem cells (NCSCs) using peripheral blood mononuclear cell-derived iPSCs and compared biological and transcriptome features under naïve culture conditions between three independent healthy control (HC) subjects and three MMD patients. VSMC transcriptome profiles were also compared to those of endothelial cells (ECs) differentiated from the same iPSCs., Results: Homogeneous spindle-shaped cells differentiated from iPSCs exhibited smooth muscle cell marker expressions, including α-smooth muscle actin (αSMA, 82.3 ± 6.7% and 81.0 ± 6.7%); calponin (91.3 ± 2.1% and 90.9 ± 1.3%); myosin heavy chain-11 (MYH11, 96.9 ± 0.7% and 97.1 ± 0.3%) without significance of differences between the two groups. Real-time PCR showed few PECAM1 and CD34 gene expressions in both groups, indicating features of differentiated VSMCs. There were no significant differences in cellular proliferation (p = 0.45), migration (p = 0.60), and contractile abilities (p = 0.96) between the two groups. Transcriptome analysis demonstrated similar gene expression profiles of VSMCs in HC subjects and MMD patients with six differentially expressed genes (DEGs); while ECs showed a distinct transcriptome profile in MMD patients with 120 DEGs. The Wnt-signaling pathway was a significant pathway in VSMCs., Conclusions: This is the first study that established VSMCs from NCSCs using MMD patient-derived iPSCs and demonstrated similar biological function and transcriptome profile of iPSC-derived VMSCs in MMD patients and HC subjects under naïve single culture condition. Comparative transcriptome features between iPSC-derived VSMCs and ECs, displaying distinct transcriptome in the ECs, suggested that pathological traits can be driven by naïve ECs predominantly and VSMCs may require specific environmental factors in MMD, which provides novel insight into the pathophysiology of MMD. Our iPSC derived VSMC model can contribute to further investigations of diagnostic and therapeutic target of MMD in addition to the current iPSC derived EC model., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Purpose: Moyamoya disease has a high incidence of cerebral vascular accident in children and adolescents, which can endanger the physical and mental health of children and adults seriously. However, the etiology and the pathogenesis of moyamoya disease remain unclear. Connexin43 (Cx43) is a predominant intercellular gap junction protein that plays an important role in the normal function of arteries and the development of several cardiovascular diseases. We aimed to preliminarily investigate pathological changes and the expression of Cx43 in cerebral arteries of patients with moyamoya disease., Materials and Methods: This study collected 10 experimental cerebral artery specimens from patients with moyamoya disease and 10 control cerebral artery specimens from patients without moyamoya disease during surgery, then pathological changes and change in Cx43 expression of cerebral artery specimens were investigated in the 2 groups by hematoxylin and eosin staining and immunofluorescence., Results: The intima of cerebral arteries was thin with monolayer endothelial cells in the control group but had asymmetrical thickening for the cerebral arteries in the experimental group. The mean ± standard deviation of the mean optical density of Cx43 in the experimental group was .065 ± .011 (range, .045-.081), whereas that in the control group was .035 ± .005 (range, .028-.042). The expression of Cx43 in the experimental group was statistically significantly higher in comparison with the control group (P < .01)., Conclusion: The abnormal expression of Cx43 in the cerebral arteries may play an important role in the formation of vascular intima thickening in patients with moyamoya disease., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

The RING finger protein 213 (RNF213) is an important susceptibility gene for moyamoya disease (MMD) and is also implicated in other types of intracranial major artery stenosis/occlusion (ICAS); however, the role of RNF213 in the development of ICAS including MMD is unclear. The constitutive expression of the RNF213 gene is relatively weak in brain tissue, while information regarding the expression patterns of the RNF213 gene under cerebral ischemia, which is one of characteristic pathologies associated with ICAS, is currently limited. Our objective was to address this critical issue, and we investigated Rnf213 mRNA expression in rat brains after 5 minutes of transient global cerebral ischemia (tGCI) by occluding the common carotid arteries coupled with severe hypotension. Rnf213 gene expression patterns were investigated with in situ RNA hybridization and a real-time polymerase chain reaction (PCR) from 1 to 72 hours after tGCI. In situ RNA hybridization revealed a significant increase in Rnf213 mRNA levels in the hippocampus CA1 sub-region 48 hours after tGCI. The significant induction of the Rnf213 gene was also evident in the ischemic cortex. Double staining of Rnf213 mRNA with NeuN immunohistochemistry revealed Rnf213 hybridization signal expression exclusively in neurons. The real-time PCR analysis confirmed the induction of the Rnf213 gene after tGCI. The up-regulation of the Rnf213 gene in vulnerable neurons in the hippocampus CA1 after tGCI suggests its involvement in forebrain ischemia, which is an underlying pathology of MMD. Further investigations are needed to elucidate its exact role in the pathophysiology of ICAS including MMD., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)