PTEN Deficiency Promotes Pathological Vascular Remodeling of Human Coronary Arteries
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE110622 | GEO | 2018/02/15
REPOSITORIES: GEO
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Project description:PTEN Deficiency Promotes Pathological Vascular Remodeling of Human Coronary Arteries
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Project description:Phosphatase and tensin homolog (PTEN) is an essential regulator of the differentiated vascular smooth muscle cell (SMC) phenotype. Our goal was to establish that PTEN loss promotes SMC dedifferentiation and pathological vascular remodeling in human atherosclerotic coronary arteries and nonatherosclerotic coronary arteries exposed to continuous-flow left ventricular assist devices (CF-LVADs). Arteries were categorized as nonatherosclerotic hyperplasia (NAH), atherosclerotic hyperplasia (AH), or complex plaque (CP). NAH coronary arteries from CF-LVAD patients were compared to NAH coronaries from non-LVAD patients. Intimal PTEN and SMC contractile protein expression was reduced compared with the media in arteries with NAH, AH, or CP. Compared with NAH, PTEN and SMC contractile protein expression was reduced in the media and intima of arteries with AH and CP. NAH arteries from CF-LVAD patients showed marked vascular remodeling and reduced PTEN and α-smooth muscle actin (αSMA) in medial SMCs compared with arteries from non-LVAD patients; this correlated with increased medial collagen deposition. Mechanistically, compared with ApoE-/- mice, SMC-specific PTEN-null/ApoE-/- double-knockout mice exhibited accelerated atherosclerosis progression and increased vascular fibrosis. By microarray and validated quantitative RT-PCR analysis, SMC PTEN deficiency promotes a global upregulation of proinflammatory and profibrotic genes. We propose that PTEN is an antiinflammatory, antifibrotic target that functions to maintain SMC differentiation. SMC loss of PTEN results in pathological vascular remodeling of human arteries.
| S-EPMC5916252 | biostudies-literature
Project description:Vascular smooth muscle cells require beta1 integrin for survival. Following the induced deletion of smooth muscle beta1 integrin, smooth muscle cells undergo apoptosis and arteries become fibrotic. This microarray study on mesenteric arteries 2 weeks after the initiation of beta1 integrin deletion specifically in smooth muscle cells of the adult mouse aimed to examine early changes in expression following deletion. Mesenteric arteries from three wild type mixed background and three beta1 integrin smooth muscle knockout mixed background mice are examined.
2013-02-26 | E-GEOD-44663 | biostudies-arrayexpress
Project description:Vascular smooth muscle cells require beta1 integrin for survival. Following the induced deletion of smooth muscle beta1 integrin, smooth muscle cells undergo apoptosis and arteries become fibrotic. This microarray study on mesenteric arteries 2 weeks after the initiation of beta1 integrin deletion specifically in smooth muscle cells of the adult mouse aimed to examine early changes in expression following deletion.
2013-02-26 | GSE44663 | GEO
Project description:Soft tissue sarcomas (STS) are a heterogeneous group of tumors associated with poor clinical outcome. While a subset of STS are characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and p53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas (HGUPS), leiomyosarcomas (LMS) and carcinosarcomas (CS) that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient whereas the wild-type allele of p53 invariably gained point mutations. Gene expression profile showed upregulated Notch signaling in Pten∆/+p53∆/+ tumors compared to Pten+/+p53∆/+. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of p53-deficient bone marrow-derived mouse mesenchymal stem cells and tumor cells, while activating the Notch pathway. Moreover, the increased oncogenic behavior of Pten∆/+p53∆/+ and shPten-transduced Pten+/+p53∆/+ tumor cells was counteracted by treatment with a gamma secretase inhibitor (GSI), suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and p53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the crosstalk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying high-grade sarcoma patients for targeted treatments. Compare Pten∆/+p53∆/+ to Pten+/+p53∆/+ high-grade undifferentiated pleomorphic sarcomas (HGUPS)
2013-01-01 | GSE42103 | GEO
Project description:Soft tissue sarcomas (STS) are a heterogeneous group of tumors associated with poor clinical outcome. While a subset of STS are characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and p53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas (HGUPS), leiomyosarcomas (LMS) and carcinosarcomas (CS) that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient whereas the wild-type allele of p53 invariably gained point mutations. Gene expression profile showed upregulated Notch signaling in PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ tumors compared to Pten+/+p53M-bM-^HM-^F/+. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of p53-deficient bone marrow-derived mouse mesenchymal stem cells and tumor cells, while activating the Notch pathway. Moreover, the increased oncogenic behavior of PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ and shPten-transduced Pten+/+p53M-bM-^HM-^F/+ tumor cells was counteracted by treatment with a gamma secretase inhibitor (GSI), suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and p53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the crosstalk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying high-grade sarcoma patients for targeted treatments. Compare PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ to Pten+/+p53M-bM-^HM-^F/+ high-grade undifferentiated pleomorphic sarcomas (HGUPS) 4 PtenM-bM-^HM-^F/+p53M-bM-^HM-^F/+ were compared to 5 Pten+/+p53M-bM-^HM-^F/+ Keywords: Differential gene expression.
2013-01-01 | E-GEOD-42103 | biostudies-arrayexpress
Project description:The project is based on the transcriptomic analysis from 8 groups of animal samples : Wild Type Sham Wild Type Castrated LXR-/- Sham LXR-/- Castrated PTEN-/- Sham PTEN-/- Castrated PTEN-/-LXR-/- Sham PTEN-/-LXR-/- Castrated.
2020-07-31 | GSE134137 | GEO
Project description:Diffuse intimal thickening (DIT) is a preclinical stage of atherogenesis in humans that does not exist in commonly used mouse models of atherosclerosis. Vascular smooth muscle cells (SMCs) are the predominant cell type that occupies the intimal and medial layers of human coronary arteries. The intimal layer of DIT is particularly prone to developing atherosclerosis later in life. Differences in the molecular features between the intimal and medial layers of DIT regions may represent the earliest changes that promote atherogenesis in humans, and can be studied by spatial molecular phenotyping.
2025-02-11 | GSE283269 | GEO
Project description:Our objective is to identify new miRNAs and their target mRNAs involved in arterial stenosis, especially pathological changes of smooth muscle cells. To this end, the balloon injury model was used to induce the activation of smooth muscle cells by damaging arterial endothelial cells. The balloon-injured rat carotid arteries were isolated and subjected to the RNA-Seq.
2022-10-01 | E-MTAB-11100 | biostudies-arrayexpress
Project description:Approximately 50% of melanomas harbor an activating BRAFV600E mutation. Standard of care involves a combination of inhibitors targeting mutant BRAF and MEK1/2, the substrate for BRAF in the MAPK pathway. PTEN loss of function mutations occur in 40% of BRAFV600E melanomas, resulting in increased PI3K/AKT activity that enhances resistance to BRAF/MEK combination inhibitor therapy. To compare the response of PTEN null to PTEN wild type cells in an isogenic background, CRISPR was used to knock out PTEN in the A375 melanoma cell line that harbors a BRAFV600E mutation. Kinome profiling was performed using the parental line and two PTEN KO clones (5 and 11), treated with DMSO, or treated with 100nM dabrafenib and 10nM trametinib for 1 day or for 7 days. PTEN KO cells showed dramatically increased binding of HER3 and AKT3 compared to wild type. The activation of the SOX10-FOXD3-HER3-AKT axis in PTEN KO cells could be targeted with the ERBB/HER inhibitor neratinib.
2024-04-23 | PXD033921 | Pride