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Rapamycin, but not propranolol, can partially revert CCM phenotype in brain endothelial cells and ameliorates chronic cavernoma development in combination with lapatinib

ABSTRACT: Brain microvascular endothelial cells (mBMEC) deficient in Ccm3 were used to model CCMs in vitro. Cells were treated with propranolol (10 µM) and rapamycin (100 nM) for various durations. RNAseq was employed to analyze gene expression. Propranolol did not significantly affect the CCM phenotype in mBMEC, failing to revert gene expression changes. Rapamycin partially reversed gene expression changes caused by Ccm3 deficiency, affecting genes such as Nos3, Adamts1, and Thbs1, known to be important for cavernoma pathogenesis in endothelial cells deficient for Ccm3. Propranolol's lack of efficacy in brain endothelial cells raises questions about its mechanism of action and potential benefits in CCM treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE298723 | GEO | 2026/07/10

REPOSITORIES: GEO

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Rapamycin, but not propranolol, can partially revert CCM phenotype in brain endothelial cells and ameliorates chronic cavernoma development in combination with lapatinib

Project description:Rapamycin, but not propranolol, can partially revert CCM phenotype in brain endothelial cells and ameliorates chronic cavernoma development in combination with lapatinib

| PRJNA1271011 | ENA

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2024-06-12 | GSE246598 | GEO

KRIT1 heterozygous mutations are sufficient to induce a pathological phenotype in patient-derived iPSC models of Cerebral Cavernous Malformation

Project description:Cerebral Cavernous Malformation (CCM) is a neurovascular disease distinguished by clusters of leaky, mulberry-like blood vessels. KRIT1 biallelic loss-of-function mutations in endothelial cells are known to trigger brain cavernomas, however, human pre-clinical models are needed to unveil the importance of germline KRIT1 heterozygous mutations in CCM pathogenesis. We generated three iPSCs from CCM patients with hereditary KRIT1 heterozygous mutations. Patient-derived vascularized organoids exhibited intricate and abnormal vascular structures with cavernoma-like morphology, and iPSCs-derived endothelial cells displayed phenotypic abnormalities at the junctional and transcriptional level. Upon injection into brain explants, CCM-endothelial cells integrated into the normal vasculature and created vascular anomalies. Lastly, transcriptional analysis showed that the endothelial progenitor marker PEG3 was highly expressed in iPSCs-derived CCM endothelial cells and further confirmed in familial and sporadic cavernoma biopsies. Overall, our study enlightens the molecular consequence of KRIT1 heterozygous mutations in endothelial cells and the potential implications in cavernoma pathogenesis.

2025-04-15 | GSE291768 | GEO

RNA-seq studies in dabrafenib treated endothelial cells

Project description:Cerebral Cavernous Malformations (CCM) constitute the second most common type of intracranial vascular malformations. Cavernomas arise due to somatic or autosomal dominant inherited loss-of-function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3), forming fragile mulberry-like malformed blood vessel structures, which are prone to leak and break. Treatment is limited to surgical removal of solitary cavernomas. As patients often present with multiple lesions, there is an urgent need to develop non-invasive therapeutic strategies. We performed a high throughput screen of 5200 bioactive molecules followed by image analysis on Ccm3-knockout endothelial cells and discovered that the FDA-EMA-approved BRAF inhibitor dabrafenib, effectively restored cell-cell junctions and vascular barrier properties of CCM-deficient endothelial cells. The potential translatability of dabrafenib was tested in vivo, where it reduced cerebral lesion burden and suppressed lesion permeability, reducing perivascular plasma protein depositions. Dabrafenib also rescued abnormal structural defects present in the developing retina vasculature. Mechanistically, dabrafenib targeted extracellular regulated kinase (ERK)5-Krüppel like factor (KLF)2/4 signaling pathway and suppressed F-actin stress fiber formation, two potentially independent and central molecular processes involved in CCM pathology. Dabrafenib is a kinase inhibitor indicated for the treatment of tumors with BRAF V600E mutations. However, silencing of BRAF did not interfere with dabrafenib-induced KLF2/4 inhibition and restoration of cell-cell junctions, suggesting that its dual therapeutic outcome is independent of BRAF pathway inhibition. In conclusion, dabrafenib is a small molecular weight compound with marked inhibitory effects on cavernoma pathogenesis suggesting that CCMs could be treated with dabrafenib to block cavernoma growth and vascular leakage.

2026-07-15 | GSE329903 | GEO

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Project description:The purpose of this study was to investigate the transcriptional regulation of endothelial cells in CCM pathology. We isolated cerebellar endothelial cells from healthy (wild-type) mice and from mice with an inducible endothelial-specific knock-out of the Ccm3 gene (Ccm3 knock-out). We prepared RNA libraries and sequenced the samples on a HiSeq2500 sequencing system with v4 chemistry from Illumina. We then performed a differential gene expression analysis to identify genes that play a role in CCM pathology.

2022-11-22 | GSE212018 | GEO

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

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

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

CRISPR/Cas9 genome editing demonstrates that CCM3 modulates endothelial miRNA expression

Project description:CCM3 regulates blood-brain-barrier integrity and vascular maturation in vivo. CCM3 loss-of-function variants predispose to cerebral cavernous malformations (CCM). Various signalling pathways are deregulated upon CCM3 depletion in endothelial cells (ECs). In this study, we established a crRNA:tracrRNA:Cas9 RNP approach to efficiently knockout CCM3 in human ECs and studied the molecular and functional effects of its long-term inactivation. Using small RNA sequencing, we show that CCM3 regulates the expression of aging‑associated miRNAs.

2019-01-18 | GSE114947 | 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.

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