Impaired neurovascular remodeling mediated by Apelin signaling and Cdc42 activity in endothelial Rbpj deficient brain arteriovenous malformation
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ABSTRACT:
PROVIDER: PRJNA926653 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23195167_1.fastq.gz | Fastqsanger.gz | |||
| SRR23195167_2.fastq.gz | Fastqsanger.gz | |||
| SRR23195168_1.fastq.gz | Fastqsanger.gz | |||
| SRR23195168_2.fastq.gz | Fastqsanger.gz | |||
| SRR23195169_1.fastq.gz | Fastqsanger.gz |
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Project description:Brain arteriovenous malformations (bAVM) are characterized by enlarged blood vessels, which direct blood through arteriovenous AV shunts, bypassing the artery-capillary-vein network and disrupting blood flow. Clinically, bAVM treatments are invasive and not routinely applicable. There is critical need to understand mechanisms of bAVM pathologies and develop pharmacological therapies. We used an in vivo mouse model of Rbpj-mediated bAVM, which develops pathologies in the early postnatal period and an siRNA in vitro system to knockdown RBPJ in human brain microvascular endothelial cells (ECs). To understand molecular events regulated by endothelial Rbpj, we conducted RNA-Seq and ChIP-Seq analyses from isolated brain ECs. Rbpj-deficient (mutant) brain ECs acquired abnormally rounded shape (with no change to cell area), altered basement membrane dynamics, and increased EC density along AV shunts, compared to controls, suggesting impaired remodeling of neonatal brain vasculature. Consistent with impaired EC dynamics, we found increased Cdc42 activity in isolated mutant ECs, suggesting that Rbpj regulates small GTPase-mediated cellular functions in brain ECs. siRNA treated, RBPJ-deficient human brain ECs displayed increased Cdc42 activity, disrupted cell polarity and focal adhesion properties, and impaired migration in vitro. RNA-Seq analysis from isolated brain ECs identified differentially expressed genes in mutants, including Apelin, which encodes a ligand for G protein-coupled receptor signaling known to influence small GTPase activity. ChIP-Seq analysis revealed chromatin loci occupied by Rbpj in brain ECs that corresponded to G-protein and Apelin signaling molecules. In vivo administration of a competitive peptide antagonist against the Apelin receptor (Aplnr/Apj) attenuated Cdc42 activity and restored EC morphology and AV connection diameter in Rbpj-mutant brain vessels. Conclusions: Our data suggest that endothelial Rbpj promotes rearrangement of brain ECs during cerebrovascular remodeling, through Apelin/Apj-mediated small GTPase activity, and prevents bAVM. By inhibiting Apelin/Apj signaling in vivo, we demonstrated pharmacological prevention of Rbpj mediated bAVM.
2023-02-01 | GSE223532 | GEO
Project description:Brain arteriovenous malformations (bAVM) are characterized by enlarged blood vessels, which direct blood through arteriovenous AV shunts, bypassing the artery-capillary-vein network and disrupting blood flow. Clinically, bAVM treatments are invasive and not routinely applicable. There is critical need to understand mechanisms of bAVM pathologies and develop pharmacological therapies. We used an in vivo mouse model of Rbpj-mediated bAVM, which develops pathologies in the early postnatal period and an siRNA in vitro system to knockdown RBPJ in human brain microvascular endothelial cells (ECs). To understand molecular events regulated by endothelial Rbpj, we conducted RNA-Seq and ChIP-Seq analyses from isolated brain ECs. Rbpj-deficient (mutant) brain ECs acquired abnormally rounded shape (with no change to cell area), altered basement membrane dynamics, and increased EC density along AV shunts, compared to controls, suggesting impaired remodeling of neonatal brain vasculature. Consistent with impaired EC dynamics, we found increased Cdc42 activity in isolated mutant ECs, suggesting that Rbpj regulates small GTPase-mediated cellular functions in brain ECs. siRNA treated, RBPJ-deficient human brain ECs displayed increased Cdc42 activity, disrupted cell polarity and focal adhesion properties, and impaired migration in vitro. RNA-Seq analysis from isolated brain ECs identified differentially expressed genes in mutants, including Apelin, which encodes a ligand for G protein-coupled receptor signaling known to influence small GTPase activity. ChIP-Seq analysis revealed chromatin loci occupied by Rbpj in brain ECs that corresponded to G-protein and Apelin signaling molecules. In vivo administration of a competitive peptide antagonist against the Apelin receptor (Aplnr/Apj) attenuated Cdc42 activity and restored EC morphology and AV connection diameter in Rbpj-mutant brain vessels. Conclusions: Our data suggest that endothelial Rbpj promotes rearrangement of brain ECs during cerebrovascular remodeling, through Apelin/Apj-mediated small GTPase activity, and prevents bAVM. By inhibiting Apelin/Apj signaling in vivo, we demonstrated pharmacological prevention of Rbpj mediated bAVM.
2023-02-01 | GSE223531 | GEO
Project description:Impaired neurovascular remodeling mediated by Apelin signaling and Cdc42 activity in endothelial Rbpj deficient brain arteriovenous malformation [RNA-seq]
| PRJNA926657 | ENA
Project description:Impaired neurovascular remodeling mediated by Apelin signaling and Cdc42 activity in endothelial Rbpj deficient brain arteriovenous malformation [ChIP-seq]
| PRJNA926658 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-02-01 | GSE223533 | GEO
Project description:First, transcriptome analysis of purified CD31+ endothelial cells (ECs) from VEGF-treated sprouting embryoid bodies showed angiogenesis as the top affected category when Apelin is not present. In addition, loss of Apelin resulted in the modulation of pathways in ECs related to vasculogenesis, cell adhesion and response to hypoxia. Ingenuity Pathway Analysis (IPA) further identified VEGFR pathway as the main upstream regulator affected in endothelial cells, closely followed by the TGFβ1 and TNF pathways, all reduced in the absence of Apelin. The most inhibited genes from the VEGFR pathway in the absence of Apelin are angiogenesis-related genes. Second, transcriptome analysis of CD31+/CD105+ ECs sorted from Apelin wild-type and Apln-depleted tumors found a significant decrease in processes associated with endothelial cell proliferation and angiogenesis in ECs sorted out of Apelin-depleted tumors using IPA. Further, IPA predicted a decrease in the adhesion of granulocytes and upstream regulator analysis showed that proteins of the TGF-superfamily, Inhibin-βA and TGF-β1, as well as C/EBP-alpha, β-Catenin, ErbB2 and EGFR are predicted to be inhibited upstream regulators in ECs isolated from Apelin-depleted tumors.
2019-05-27 | GSE100293 | GEO
Project description:Background: Pericytes are capillary-associated mural cells especially prominent in the central nervous system where they regulate vascular permeability and blood-brain barrier integrity. Despite their relevance for neurovascular unit homeostasis and their involvement in the pathobiology of neurodegenerative diseases, signalling mechanisms responsible for functional specialization and intercellular communication remain elusive. Objectives: The main goal of this study is to understand the relevance of Rbpj (the common downstream mediator of Notch signalling, an important mediator of cell-to-cell communication) in brain pericytes and to identify molecular signatures associated to Rbpj deletion. Methods: We used mouse genetic experiments to knockout Rbpj specifically in pericytes using a mural cell-specific Cre-driver (PdgfrbCreERT2). Inclusion of the Rpl22-HA (RiboTag) construct allowed Cre-mediated HA-labeling of ribosomal proteins and consequent isolation of actively translating mRNA from pericytes. PdgfrbCreERT2 transgenic mice were used to drive recombination of Rpl22-HA (RiboTag) allele and/or Rbpj-lox conditional knockout. Tamoxifen administration from postnatal day 1 (P1) to P3 allowed efficient recombination in pericytes. Brain cortices were collected at P7 or P10 and HA-tagged polyribosomes were immunoprecipitated using anti-HA coated beads. Total RNA was extracted and sequencing libraries prepared. Results: Pericyte-specific Rbpj deletion induces severe changes in the neurovascular unit characterized by defects in vascular morphogenesis, brain hemorrhaging, altered extracellular matrix composition and strong inflammatory responses. Analysis of pericytes translatome of Rbpj-KO mice compared to controls revealed profound changes in pericyte identity, increased expression of vascular smooth muscle cell markers and increased signaling through TGFbeta, among other alterations in mural cell behavior.
2019-05-11 | GSE117083 | GEO
Project description:Background: Pericytes are capillary-associated mural cells especially prominent in the central nervous system where they regulate vascular permeability and blood-brain barrier integrity. Despite their relevance for neurovascular unit homeostasis and their involvement in the pathobiology of neurodegenerative diseases, signalling mechanisms responsible for functional specialization and intercellular communication remain elusive. Objectives: The main goal of this study is to understand the relevance of Rbpj (the common downstream mediator of Notch signalling, an important mediator of cell-to-cell communication) in brain pericytes. In particular, the ChIP-Seq results aimed at the identification of genes bound to RBPJ in cultured mouse brain pericytes.
2019-05-12 | GSE120482 | GEO
Project description:Evaluation of microRNAs that are downstream of apelin/APJ signaling in the pulmonary artery endothelial cells. Triplicates per group, subjected to: 1) control siRNA, 2) apelin siRNA, 3) APJ siRNA, 4) apelin + APJ siRNA
2012-12-04 | E-GEOD-42343 | biostudies-arrayexpress
Project description: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.
2025-08-07 | GSE287906 | GEO