Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations
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PROVIDER: PRJNA802027 | ENA |
REPOSITORIES: ENA
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Project description:Purpose: Cerebral cavernous malformations (CCMs) are hemorrhagic neurovascular malformations that may lead to stroke, seizures and other clinical sequelae. Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis; however, it remains unclear how these mutations contribute to sporadic versus familial cases. In our previous research, we’ve shown that co-occurring MAP3K3 and PIK3CA mutations are present within the same clonal population of cells. The overall goal of this study was to identify PIK3CA mutations in CCM-associated developmental venous anomalies (DVA). We also analyzed the plasma miRNome of patients with (1) DVA without associated CCM, as well as (2) DVA with an associated CCM) to identify circulating miRNAs that might serve as biomarkers reflecting PIK3CA activity. Methods: We collected and sequenced the plasma miRNome of 12 individuals with a sporadic CCM associated with a DVA (CCM + DVA), 6 individuals with a DVA without a CCM (DVA only), and 7 healthy controls. Results: We found that the identical PIK3CA mutation is found in endothelial cells of both the DVA and its associated CCM, but that an activating MAP3K3 mutation appears only in the CCM. The analyses miR-134-5p was downregulated in the groups of patients with only a DVA only group (when compared to healthy controls). This miRNA has been shown to target PIK3CA. In addition, miR-182-5p, was upregulated and targets MAP3K3; while let-7c-5p was downregulated and targets both PIK3CA and MAP3K3 in the group of patients with CCM and an associated DVA (when compared to DVA only). Conclusions: These results support a mechanism where DVA develop as the result of a PIK3CA mutation, creating a region of the brain vasculature that functions as a genetic primer for CCM development following acquisition of an additional somatic mutation.
2022-02-06 | GSE195732 | GEO
Project description:Cerebral cavernous malformations are vascular anomalies that can cause hemorrhagic stroke. Mutations in genes encoding Krit 1 (CCM1), OSM (CCM2), and PDCD10 (CCM3) proteins cause CCM. A loss in teh expression of any of these CCM proteins disrupts normal cerebral vessel development by disrupting the cytoskeleton and thereby inhibits endothelial tube ofrmation. Examination of cellular changes based on the loss of CCM gene expression may lead to the methods for early detection and prevention of CCM associated hemorrhagic stroke.
2014-06-09 | PXD000362 | Pride
Project description: Not available
| S-EPMC3850546 | biostudies-literature
Project description:Distinct endothelial cell cycle states (early G1 vs. late G1) provide different “windows of opportunity” to enable the differential expression of genes that regulate venous and arterial specification, respectively. Endothelial cell cycle control and arterial-venous identities are disrupted in vascular malformations including arteriovenous (AV) shunts which is a hallmark of hereditary hemorrhagic telangiectasia (HHT). We show how endothelial cell late G1 arrest induced by Palbociclib modulates the expression of genes regulating arterio-venous identity and prevents AVM development induced by BMP9/10 inhibition.
2023-12-31 | GSE245197 | GEO
Project description:Objective: Vascular malformations affect 3% of neonates. Venous malformations (VMs) are the largest group representing more than 50 % of cases. In hereditary forms of VMs gene mutations have been identified, but for the large group of spontaneous forms the primary cause and downstream dysregulated genes are unknown. Methods and Results: We have performed a global comparison of gene expression in slow-flow VMs and normal saphenous veins using human whole genome micro-arrays. Genes of interest were validated with qRT-PCR. Gene expression in the tunica media was studied after laser micro-dissection of small pieces of tissue. Protein expression in endothelial cells (ECs) was studied with antibodies. We detected 511 genes more than 4-fold down- and 112 genes more than 4-fold up-regulated. Notably, chemokines, growth factors, transcription factors and regulators of extra-cellular matrix (ECM) turnover were regulated. We observed activation and arterialization of ECs of the VM proper, whereas ECs of vasa vasorum exhibited up-regulation of inflammation markers. In the tunica media, an altered ECM turnover and composition was found. Conclusions: Our studies demonstrate dysregulated gene expression in tunica interna, media and externa of VMs, and show that each of the three layers represents a reactive compartment. The dysregulated genes may serve as therapeutic targets. Keywords: disease analysis
2007-03-06 | GSE7190 | GEO
Project description:Objective: Vascular malformations affect 3% of neonates. Venous malformations (VMs) are the largest group representing more than 50 % of cases. In hereditary forms of VMs gene mutations have been identified, but for the large group of spontaneous forms the primary cause and downstream dysregulated genes are unknown. Methods and Results: We have performed a global comparison of gene; expression in slow-flow VMs and normal saphenous veins using human whole genome micro-arrays. Genes of interest were validated with qRT-PCR. Gene expression in the tunica media was studied after laser micro-dissection of small pieces of tissue. Protein expression in endothelial cells (ECs) was studied with antibodies. We detected 511 genes more than 4-fold down- and 112 genes more than 4-fold up-regulated. Notably, chemokines, growth factors, transcription factors and regulators of extra-cellular matrix (ECM) turnover were regulated. We observed activation and arterialization of ECs of the VM proper, whereas ECs of vasa vasorum exhibited up-regulation of inflammation markers. In the tunica media, an altered ECM turnover and composition was found. Conclusions: Our studies demonstrate dysregulated gene expression in tunica interna, media and externa of VMs, and show that each of the three layers represents a reactive compartment. The dysregulated genes may serve as therapeutic targets. Experiment Overall Design: - 4 samples Experiment Overall Design: - samples are replicates with dye swap
2008-06-15 | E-GEOD-7190 | biostudies-arrayexpress
Project description:Cerebral cavernous malformation (CCM) is a rare neurovascular disease that is characterized by enlarged and irregular blood vessels that often lead to cerebral hemorrhage. Loss-of-function mutations to any of three genes results in CCM lesion formation; namely, CCM1, CCM2, and CCM3. Here, we report for the first time in-depth single-cell RNA sequencing, combined with spatial transcriptomics and immunohistochemistry, to comprehensively characterize subclasses of brain endothelial cells under both normal conditions and after deletion of Ccm3 in a mouse model of CCM. Integrated single-cell analysis identifies arterial endothelial cells as refractory to CCM transformation. Conversely, a subset of angiogenic venous capillary endothelial cells and respective resident endothelial progenitors is at the origin of CCM lesions. These data are relevant for the understanding of the plasticity of the brain vascular system and provide novel insights into the molecular basis of CCM disease at the single cell level.
2020-11-04 | GSE155788 | GEO
Project description:Cerebral cavernous malformations (CCM) are vascular malformations associated with abnormally dilated blood vessels and leaky capillaries that often result in hemorrhages. Despite recent advances, precise understanding of the cellular and molecular mechanism leading to the pathogenesis of CCM remains elusive. Emerging evidence indicates that small nucleolar RNAs (snoRNAs), belonging to the class of non-coding RNAs, may play a significant role as diagnostic markers in human diseases. However, there is no report till date that studied the role of snoRNAs in CCM biology. The objective of the current study was to identify snoRNAs associated with CCM pathogenesis. Using genome-wide small RNA sequencing, we identified a total of 271 snoRNAs reliably expressed in CCM. By applying additional statistical stringency, three snoRNAs (SNORD115-32, SNORD114-22 and SNORD113-3) were found to be significantly downregulated in CCM patient tissue samples (n = 3) as compared to healthy brains (n = 3). Deregulation of the selected snoRNAs was further validated by qRT-PCR. Further, cellular localization via in situ hybridization also confirmed robust reduction in the expression of SNORD115-32 and SNORD114-22 in CCM tissues as compared to the healthy controls. By applying high throughput sequencing and cellular localization analyses, we report here for the first time the genome-wide expression profile of snoRNAs in CCM tissues and a robust downregulation of candidate snoRNAs in CCM conditions. Future studies should warrant the screening in large CCM patient cohorts and will be helpful in the development of potential biomarkers and improved clinical diagnosis.
2018-12-31 | GSE111623 | GEO
Project description:Genome-Wide Sequencing Reveals Small Nucleolar RNAs Downregulated in Cerebral Cavernous Malformations
| PRJNA437595 | ENA