Single cell lineage tracing of pulmonary endothelial cells in mouse model of Hereditary Hemorrhagic Telangiectasia 2
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE269174 | GEO | 2025/02/12
REPOSITORIES: GEO
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Project description:Arteriovenous malformations (AVMs) are characteristic of hereditary hemorrhagic telangiectasia (HHT). We used single cell RNA sequencing (scRNA-seq) to analyzed the pulmonary ECs in mice with endothelial-specific deletion of Alk1 gene.
2025-02-12 | GSE242741 | GEO
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:Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant vascular dysplasia characterized by epistaxis, mucocutaneous telangiectases, and arteriovenous malformations (AVM) in visceral organs. In this study, we carried out a liquid biopsy consisting in the isolation of total RNA from plasma exosomes samples from HHT type 1 (HHT1 group) and type 2 (HHT2 group) patients, and healthy relatives (Control group). Upon gene expression data processing and normalization, a bioinformatics analysis was performed for the study of principal components, hierarchical clustering and pairwise comparisons between HHT samples and control group. Results were evaluated in a further validation cohort of HHT and healthy donors by real time PCR and the diagnosis value of exosomal miRNA determined by the ROC curves analysis. We found that exosomal miRNA expression signature clearly distinguishes among healthy and HHT samples and types. Thus, we identified a disease-associated molecular fingerprint of 35 miRNAs over-represented, being 8 specifics for HHT1 and 11 for HHT2; and 30 under-represented, including 9 distinctive for HHT1 and 9 for HHT2. These exosome-transported miRNAs have diagnosis value for HHT, and even allow to distinguish between HHT1 and HHT2.
2021-09-28 | GSE179382 | GEO
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.
2014-12-19 | E-GEOD-53515 | biostudies-arrayexpress
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-β signalling pathway. Further knowledge on how a disturbance of the TGF-β 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.
2014-12-19 | GSE53515 | GEO
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.
2024-07-31 | GSE252666 | GEO
Project description:Purpose: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder characterized by arteriovenous malformations (AVMs). Over 90% of HHT patients carry heterozygous loss-of-function mutations in Transforming Growth Factor-beta (TGFb) signaling components activin receptor-like kinase 1 (ACVRL1/ALK1), endoglin (ENG), or mothers against decapentaplegic homolog 4 (SMAD4). Brain AVMs can be lethal for HHT patients. Here, we use an inducible endothelial (EC)-specific mouse line to investigate brain AVMs characteristics in Alk1-, Eng-, and Smad4-HHT mouse models. Angiopientin-2 (Ang2) inhibition diminishes HHT associated cerebral vascular defects. We aim to identify the shared transcriptional changes in brain ECs between these three HHT types, and provide insights for transcriptional changes upon Ang2 inhibition. Methods: ECs were isolated from brains of both WT and HHT mutant mice at postnatal day 7 (P7) for Smad4 and Eng models, P6 for Alk1 model. Total RNA was extracted from isolated brain ECs and quantified using Qubit RNA High Sensitivity Assay Kit. RNA integrity was determined using the Bioanalyzer RNA 6000 Nano assay kit. RNA library construction was performed with the TruSeq RNA Library Prep Kit v2 from Illumina. The resulting mRNA library was quantified using Qubit dsDNA High Sensitivity Assay Kit and verified using the Bioanalyzer DNA1000 assay kit. Verified samples were sequenced using the NextSeq 500/550 High Output Kit v2.5 (150 Cycles) on a Nextseq 550 system. Sequenced reads were aligned to the mouse (mm10) reference genome with RNA-seq alignment tool (version 2.0.1). The aligned reads were used to quantify mRNA expression and determine differentially expressed genes using the RNA-seq Differential Expression tool (version 1.0.1). Both alignment and differential expression analysis were performed using the tools in the BaseSpace Sequence Hub. Results: We identified 5509, 5381, and 2663 differentially expressed genes in Smad4, Alk1, and Eng HHT models respectively. Also, Ang2 inhibition mainly funcioned through angiogenesis and cell migration processes to normalize cerebrovascular defects in Smad4-HHT model. Conclusions: A common but unique pro-angiogenic program among all HHT models included 14 consistent upregulated and 5 consistent downregulated angiogic genes. Also, Ang2 inhibition mainly funcioned through angiogenesis and cell migration processes to normalize cerebrovascular defects in Smad4-HHT model.
2023-05-19 | GSE197105 | GEO
Project description:Hereditary hemorrhagic telangiectasia (HHT) is an inherited autosomal dominant disorder associated with mutations in the bone morphogenetic protein (BMP) pathway. Inherited heterozygous loss of function mutations and acquired loss of heterozygosity in either Alk1, Eng, or Smad4 lead to the development of arteriovenous malformations (AVMs), which trigger local vessel instability, hypoxia and vessel leakage or rupture. Current models assume common cellular pathomechanisms culminating in altered endothelial cell (EC) shape regulation, directional migration and proliferation control as a consequence of deficient BMP pathway signaling in ECs under the influence of blood-flow mediated shear stress. Here we report that loss of Alk1 or Smad4 surprisingly triggers very distinct endothelial phenotypes, signaling dynamics and transcriptional changes in ECs, both in vitro and in vivo. EC behavior in both in vivo and mosaic flow cultures illustrate that cells deficient in Smad4 effectively migrate against the direction of fluid shear, from veins to arteries, whereas cells lacking Alk1 fail to polarize and migrate against flow. Our data suggest that AVMs triggered by Smad4 mutations occur through hyperpruning of capillaries, thus precipitating flow in a single shunt, whereas AVMs caused by Alk1 mutation grow by cell accumulations close to the vein, as well as the persistence of a hyperdense plexus that drives nidus formation. We propose that the cellular pathomechanisms leading to AVM formation are not the same if the upstream BMP receptor Alk1, or the downstream common transcription factor Smad4 are mutated, raising the prospect for urgently needed, mechanism-based, therapeutic avenues that need to be tailored to correcting the specific pathomechanism.
2025-02-18 | GSE282952 | GEO
Project description:BMP9 signaling has been implicated in hereditary hemorrhagic telangiectasia and vascular remodeling, acting via the HHT target genes, endoglin and ALK1. This study sought to identify endothelial BMP9-regulated proteins that could affect the HHT phenotype. Gene ontology analysis of cDNA microarray data obtained following BMP9 treatment of primary human endothelial cells indicated regulation of chemokine, adhesion, and inflammation pathways. The sample set is comprised of three biological replicate control human dermal microvascular endothelial cells, and three treated (5 ng/ml human recombinant BMP9) biological replicate human dermal microvascular endothelial cells
2012-09-19 | E-GEOD-40960 | biostudies-arrayexpress
Project description:BMP9 signaling has been implicated in hereditary hemorrhagic telangiectasia and vascular remodeling, acting via the HHT target genes, endoglin and ALK1. This study sought to identify endothelial BMP9-regulated proteins that could affect the HHT phenotype. Gene ontology analysis of cDNA microarray data obtained following BMP9 treatment of primary human endothelial cells indicated regulation of chemokine, adhesion, and inflammation pathways.
2012-09-19 | GSE40960 | GEO