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Gene expression profile after CCM1 over expression in human umbilical vein endothelial cells

ABSTRACT: CCM1 (also known as KRIT1) is critical regulator of endothelial cell biology. Mutations in CCM1 can lead to the formation of cerebral cavernous malformations (CCM). CCM lesions are frequent in the human population; however, their pathogenesis is poorly understood. This genome-wide expression analysis is aimed to unravelling novel mechanisms how CCM1 executes its functions in endothelial cells. We used human umbilical vein endothelial cells (HUVEC) as a model system to study CCM1 functions after adenoviral over expression. The results of this experiment suggest that CCM1 is a critical regulator of endothelial cell cycle control and proliferation as well as migration and angiogenesis. This fits well to the roles of CCM1 in HUVEC which indeed acts as a negative regulator of angiogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE18014 | GEO | 2010/06/08

SECONDARY ACCESSION(S): PRJNA119243

REPOSITORIES: GEO

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Gene expression profile after CCM1 over expression in human umbilical vein endothelial cells

Project description:CCM1 (also known as KRIT1) is critical regulator of endothelial cell biology. Mutations in CCM1 can lead to the formation of cerebral cavernous malformations (CCM). CCM lesions are frequent in the human population; however, their pathogenesis is poorly understood. This genome-wide expression analysis is aimed to unravelling novel mechanisms how CCM1 executes its functions in endothelial cells. We used human umbilical vein endothelial cells (HUVEC) as a model system to study CCM1 functions after adenoviral over expression. The results of this experiment suggest that CCM1 is a critical regulator of endothelial cell cycle control and proliferation as well as migration and angiogenesis. This fits well to the roles of CCM1 in HUVEC which indeed acts as a negative regulator of angiogenesis. Human umbilical vein endothelial cells were transduced with adenovirus expressing CCM1 or GFP as control. 48 hours after transduction total RNA was isolated from duplicates for genome-wide expression analysis biological replicate: GFP rep1, GFP rep2 biological replicate: CCM1 rep1, CCM1 rep2

2010-06-16 | E-GEOD-18014 | biostudies-arrayexpress

Expression profiling after ICAP1 or constitutive active NOTCH1 over expression in human umbilical vein endothelial cells

Project description:ICAP1 (also known as ITG1BP1) is a protein interaction partner of beta1-integrins and the cerebral cavernous malformation protein 1 (CCM1, also known as KRIT1). In mice Icap1 plays an important role for bone development. The function of ICAP1 in endothelial cells is poorly understood. However, the interactions with beta1-integrins and CCM1 suggest that ICAP1 should play an important role also in endothelial cells. We obtained data that ICAP1 might activate the Delta-Notch signaling cascade, a critical regulator of endothelial proliferation, migration and sprouting angiogenesis. This genome-wide expression analysis is aimed to unravelling novel mechanisms or signaling pathways how ICAP1 functions in endothelial cells. Secondly, this study aimed at defining novel target genes of Notch signaling and finally to compare the gene expression patterns of ICAP1 and NOTCH1. We used human umbilical vein endothelial cells (HUVEC) as a model system to study ICAP1 and NOTCH1 functions after adenoviral over expression in comparison to GFP over expression as control. The results of this experiment suggest that ICAP1 and NOTCH1 control a series of genes involved in cell proliferation, migration and angiogenesis. A high proportion of ICAP1-regulated genes is also regulated by NOTCH1 in a very similar manner. Human umbilical vein endothelial cells were transduced with adenovirus expressing ICAP1, NOTCH1 (only the constitutive active intracellular domain) or GFP as control. 36 hours after transduction total RNA was isolated from duplicates for genome-wide expression analysis biological replicate: GFP_1, GFP_2 biological replicate: NOTCH1_1, NOTCH1_2 biological replicate: ICAP1_1, ICAP1_2

2010-07-30 | E-GEOD-18035 | biostudies-arrayexpress

Expression profiling after ICAP1 or constitutive active NOTCH1 over expression in human umbilical vein endothelial cells

2010-07-02 | GSE18035 | GEO

Epigenetic regulation by Polycomb Repressive Complex 1 promotes Cerebral Cavernous Malformations

Project description:Cerebral cavernous malformations (CCMs) are anomalies that develop mainly in the cerebral vasculature. They result from mutations in CCM1/KRIT1, CCM2, or CCM3/PDCD10. Loss of CCM proteins triggers a MAPK-Krüppel-like factor 2 (KLF2) signaling cascade, which induces a pathophysiological pattern of gene expression within endothelial cells. The downstream target genes that are activated by KLF2 are mostly unknown. Here we show that Chromobox Protein Homolog 7 (CBX7), component of the Polycomb Repressive Complex 1, contributes to pathophysiological KLF2 signaling during zebrafish cardiovascular development. CBX7/cbx7a mRNA is strongly upregulated in lesions of CCM patients, and in human, mouse, and zebrafish CCM-deficient endothelial cells. The silencing or pharmacological inhibition of CBX7/Cbx7a suppresses pathological CCM phenotypes in ccm2 zebrafish, CCM2-deficient HUVECs, and in a pre-clinical murine CCM3 disease model. Whole-transcriptome datasets from zebrafish cardiovascular tissues and human endothelial cells reveal that CBX7/Cbx7a plays a role in the activation of KLF2 targets including genes encoding TEK, Angiopoietin1, WNT9, and endoMT proteins. Our findings uncover an intricate interplay in the regulation of Klf2-dependent biomechanical signaling by CBX7 in CCM. This work also provides insights for therapeutic strategies in the pathogenesis of CCM.

2024-09-20 | GSE277234 | GEO

Cerebral Cavernous Malformation Proteins and MEKK3 Coordinately Modulate SMURF1 Abundance to Control RhoA-dependent Endothelial Cell Phenotypic State

Project description:Cerebral Cavernous Malformations (CCM), caused by loss of CCM1, CCM2 or CCM3 in endothelial cells (ECs), are leaky capillaries causing seizures and stroke. CCM protein loss gives overlapping changes in biomechanical and transcriptional properties of ECs, due to common RhoA-driven alterations in cytoskeletal organization and intracellular signaling. However, EC models of 3-D tube formation show loss of each CCM protein generates distinct morphological defects in tubular structures. Computational modeling, live-cell imaging and RNA sequencing revealed distinct functional roles of CCM1 and CCM3 in regulating EC-EC and EC-matrix interactions. CCM2 has an intermediate phenotype consistent with its interaction with CCM1 and CCM3. In ECs, CCM proteins regulate SMURF1 E3 ligase ubiquitination and degradation of RhoA. Loss of CCM proteins results in loss of SMURF1 and a concomitant increase of MEKK3, a negative regulator of SMURF1 expression. We propose CCM lesions develop because of dysregulated SMURF1 resulting in RhoA and MEKK3 gain-of-function.

2019-04-05 | GSE112882 | GEO

Expression profiling in brain microvascular endothelial cells and astrocytes in mouse models of Cranial Cavernous Malformation disease

Project description:Cerebral Cavernous Malformations (CCMs) are neurovascular lesions caused by loss-of-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3). Following onset, disease severity ranges from minimal vascular defects to numerous vascular dilations (lesions) distributed throughout the brain. Although the precise pathogenic mechanisms resulting in such a broad range of disease severity are unknown, inter-cellular communication between heterogeneous brain cell types including microvascular endothelial cells, astrocytes, and neurons are likely important in disease progression. To further understand these cell type relationships in the context of CCM, Riboseq was performed in astroctytes and mRNA expression profiling was performed from whole brain extracts as well as isolated brain microvascular endothelial cells.

2022-10-01 | GSE204979 | GEO

Thrombospondin1 replacement prevents cerebral cavernos malformations

Project description:We have purified primary brain microvascular endothelial cells (BMEC) from mice bearing floxed alleles of Krit1 (Krit1fl/fl) and an endothelial specific tamoxifen-regulated Cre recombinase (Pdgfb-iCreERT2), and used these to delete Krit1 in a time-controlled manner (Krit1ECKO). To elucidate the pathogenesis of cerebral cavernous malformations (CCM) we used genome-wide RNA sequencing (RNA-seq) to characterize the transcriptome of primary BMEC following acute genetic inactivation of Krit1.

2017-09-25 | GSE85657 | GEO

A mechano-dependent senescence associated secretory phenotype triggers the recruitment of endothelial and immune cells by Cerebral Cavernous Malformation 2 deficient endothelial cells

Project description:Cerebral Cavernous Malformations (CCM) is a cerebrovascular disease in which stacks of dilated haemorrhagic blood-filled capillaries form focally in the brain. Endothelial loss-of-function mutations on any of the three CCM genes (CCM1-3) are responsible for the familial form of the disease. Whether and how the defective mechanotransduction, inflammatory response and mosaic state characteristic of these lesions interplay to sustain the progression of CCM diseases is unknown. Here, we show that CCM1- and CCM2-silenced endothelial cells enter into a senescence associated with secretory phenotype (SASP) that they use to invade the extracellular matrix and attract surrounding wild-type endothelial and immune cells. Further, we demonstrate that this SASP is driven by the mechanical and molecular disorders provoked by ROCKs dysfunctions when CCM2 is lost. This discovery reconciles all the known dysregulated traits of CCM1/2-deficient endothelial cells into a unique mechano-dependent SASP that links perturbed cellular mechanics to microenvironment remodelling and long-range activation of WT endothelial and immune cells.

2023-07-26 | GSE165406 | GEO

Systems Biology Proteomic Analysis of Cerebral Cavernous Malformation

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

Mapping endothelial-cell diversity in cerebral cavernous malformations at single cell resolution

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

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