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Gene expression analysis in control and HIF-2 alpha deficient murine lung endothelial cells under hypoxia

ABSTRACT: Journal : Blood. 2009 Jul 9;114(2):469-77. Epub 2009 May 13. Title : Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis. Authors : Skuli N, Liu L, Runge A, Wang T, Yuan L, Patel S, Iruela-Arispe L, Simon MC, Keith B. Abstract : Hypoxia-inducible factor-2alpha (HIF-2alpha) is highly expressed in embryonic vascular endothelial cells (ECs) and activates the expression of target genes whose products modulate vascular function and angiogenesis. In this report, we describe a genetic model designed to test the physiologic consequences of deleting HIF-2alpha in murine endothelial cells. Surprisingly, mice with HIF-2alpha-deficient ECs developed normally but displayed a variety of phenotypes, including increased vessel permeability, aberrant endothelial cell ultrastructure, and pulmonary hypertension. Moreover, these animals exhibited defective tumor angiogenesis associated with increased hypoxic stress and tumor cell apoptosis. Immortalized HIF-2alpha-deficient ECs displayed decreased adhesion to extracellular matrix proteins and expressed reduced levels of transcripts encoding fibronectin, integrins, endothelin B receptor, angiopoietin 2, and delta-like ligand 4 (Dll4). Together, these data identify unique cell-autonomous functions for HIF-2alpha in vascular endothelial cells. Keywords: Murine lung endothelial cell study

ORGANISM(S): Mus musculus

PROVIDER: GSE16067 | GEO | 2009/07/15

SECONDARY ACCESSION(S): PRJNA115489

REPOSITORIES: GEO

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Gene expression analysis in control and HIF-2 alpha deficient murine lung endothelial cells under hypoxia

Project description:Journal : Blood. 2009 Jul 9;114(2):469-77. Epub 2009 May 13. Title : Endothelial deletion of hypoxia-inducible factor-2alpha (HIF-2alpha) alters vascular function and tumor angiogenesis. Authors : Skuli N, Liu L, Runge A, Wang T, Yuan L, Patel S, Iruela-Arispe L, Simon MC, Keith B. Abstract : Hypoxia-inducible factor-2alpha (HIF-2alpha) is highly expressed in embryonic vascular endothelial cells (ECs) and activates the expression of target genes whose products modulate vascular function and angiogenesis. In this report, we describe a genetic model designed to test the physiologic consequences of deleting HIF-2alpha in murine endothelial cells. Surprisingly, mice with HIF-2alpha-deficient ECs developed normally but displayed a variety of phenotypes, including increased vessel permeability, aberrant endothelial cell ultrastructure, and pulmonary hypertension. Moreover, these animals exhibited defective tumor angiogenesis associated with increased hypoxic stress and tumor cell apoptosis. Immortalized HIF-2alpha-deficient ECs displayed decreased adhesion to extracellular matrix proteins and expressed reduced levels of transcripts encoding fibronectin, integrins, endothelin B receptor, angiopoietin 2, and delta-like ligand 4 (Dll4). Together, these data identify unique cell-autonomous functions for HIF-2alpha in vascular endothelial cells. Keywords: Murine lung endothelial cell study Cnt1,2 and 3 (Hif-2a floxed/floxed) cells were subjected to 0.5% oxygen treatment for 16hrs and KO1,2 and 3 (Hif-2a knockout) cells were subjected to 0.5% oxygen treatment for 16hrs.

2009-07-15 | E-GEOD-16067 | biostudies-arrayexpress

Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth

Project description:<p>The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer. </p>

2020-06-29 | MTBLS1764 | MetaboLights

Regulation of gene expression by HIF-2alpha in multiple myeloma

Project description:Proliferation of neoplastic plasma cells within the bone marrow leads to reduced oxygen availability. In response to hypoxia, the transcription factor hypoxia-inducible factor-2alpha (HIF-2α) is activated and stabilised. We hypothesise that activation of HIF-2α is a central driver of multiple myeloma disease progression, leading to the induction of transcription of genes associated with angiogenesis, osteoclast activation and cell migration. In this study we assessed the affects of HIF-2α overexpression on gene expression in the human myeloma cell line LP-1.

2017-08-04 | GSE102235 | GEO

ChIP-seq of H3K27acethylation of human aortic endothelial cells (HAECs) treated with Cobalt chloride (CoCl2)

Project description:Endothelial-to-mesenchymal transition (EndMT) is a fundamental process in vascular remodeling, and hypoxia is known to induce EndMT and involved in cardiovascular disease development. Cobalt chloride (CoCl2), a chemical inducer of hypoxia-inducible factor-1 (HIF-1) could influence cellular function and its differentiation. However, exact molecular mechanism how stabilization of HIF-1 by cobalt chloride in human primary ECs affects cellular behavior and EndMT process is largely unknown. In this study, we performed ChIP-seq for H3K27ac in human aortic endothelial cells (HAECs) treated with CoCl2

2021-11-18 | GSE189071 | GEO

HIF-1alpha and HIF-2alpha ChIP-chip profiling in intestinal epithelial cells

Project description:Intestinal epithelia exist in a uniquely dynamic oxygen tension microenvironment. Adaptive responses to hypoxia in mammalian cells are regulated largely by hypoxia inducible factor (HIF) transcriptional complexes. Functional HIF exists as an obligate alpha/beta heterodimer, comprising both a constitutive subunit (HIF-1beta), and an oxygen-labile regulatory (alpha) component. To date, three regulatory subunits have been identified, namely HIF-1alpha, HIF-2alpha, and HIF-3alpha, with the highest level of sequence homology conserved between HIF-1alpha and HIF-2alpha. Despite their concurrent expression in intestinal epithelial cells, HIF-1 and HIF-2 play non-redundant roles in the regulation of an overlapping but distinct set of gene targets. In this study, we performed ChIP-on-chip analysis of chromatin isolated from hypoxic intestinal epithelia to delineate HIF-1 and HIF-2 specific loci. Comparison of HIF-1alpha ChIP-chip and HIF-2alpha ChIP-chip to map HIF-1- and HIF-2-specific gene targets across the genome.

2013-11-05 | E-GEOD-43108 | biostudies-arrayexpress

HIF-1alpha and HIF-2alpha ChIP-chip profiling in intestinal epithelial cells

2013-11-05 | GSE43108 | GEO

Stub1 acetylation by CBP/p300 attenuates chronic hypoxia-induced pulmonary hypertension by suppressing HIF-2α transcriptional activity

Project description:Chronic hypoxia induces pulmonary vascular remodeling and pulmonary hypertension (PH). While it is established that transcription factors, hypoxia-inducible factors (HIF-1α/HIF-2α) activate gene programs that drive hypoxia-induced PH, the mechanism of HIF-1/2 activation is less clear. Here, we report that carboxylterminus of Hsp70-interacting protein (CHIP or Stub1) modulates HIF-1α and HIF-2α transcription rather than reducing their stability. Knocking-down Stub1 reduced hypoxic activation of HIF-1α mRNA, protein, and activity while enhancing hypoxic induction of HIF-2α mRNA, protein, and target genes in pulmonary vascular cells. Mechanistically, CBP/p300-mediated acetylation of lysine (K287) inactivates the ubiquitin ligase activity of Stub1 and triggers its translocation from the cytoplasm into the nucleus. There, it recognizes the HIF promoter and hypoxia response elements (HREs) in target genes. Expression of Stub1-K287Q mutant (mimicking acetylation) enhanced hypoxia-induced HIF-1α expression, while acetyl-deficient Stub1-K287R mutant had the opposite effect on HIF-α but enhanced hypoxia-induced HIF-2α transcriptional activity. Endothelial-Stub1 transgenic mice tolerated chronic hypoxia better, had less pulmonary vascular remodeling, reduced pulmonary vascular resistance, and greater cardioprotection. Thus, Stub1 nuclear translocation enhances hypoxic induction of HIF-1α activity while suppressing deleterious effects of HIF-2α. These observations indicate that nuclear-Stub1 synergizes with HIF-1α to promote transcriptional responses and antagonizes HIF2α-driven PH in chronic hypoxia.

2023-04-01 | GSE221264 | GEO

A YAP/TAZ-TEAD signaling module links endothelial nutrient acquisition to angiogenic growth

Project description:Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue's metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are dictated by YAP/TAZ-TEAD – a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2, and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fueling nutrient mTORC1 signaling. By orchestrating the transcription of a repertoire of cell-surface transporters, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 pathway activation. Dissociating mTORC1 from these nutrient inputs – elicited by the loss of Rag GTPases – inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. These findings define a pivotal role for YAP/TAZ-TEAD in steering endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.

2022-05-08 | PXD026872 | Pride

The Inflammatory Response to Stress and Angiogenesis in Liver Resection

Project description:Patients with resectable liver metastases of colorectal origin will be assigned to laparoscopic liver resection or conventional open liver surgery. Blood samples will be drawn preoperatively and 24 hours after resection. Determination of Interleukin-6 (IL-6) and IL-8 will be done to assess the stress response between open and laparoscopic liver resection (Elisa test). The Messenger Ribonucleic Acid (mRNA) of inflammation related factors (cyclooxygenase-2 (COX-2) and Matrix metalloproteinase (MMP-9)), angiogenesis related factor (vascular endothelial growth factor (VEGF) and hypoxia induced factor-1 (HIF-1)) in tumor tissue and normal liver parenchyma will be detected by real-time real time-Polymerase Chain Reaction (RT-PCR).

| 2242738 | ecrin-mdr-crc

Gene expression analysis in primary human renal tumors, categorized by VHL genotype and HIF-alpha expression

Project description:Human renal cell carcinomas (RCC) have differential expression of HIF-1alpha and HIF-2alpha, depending on VHL genotype and other events. Here, we have divided a series of RCC samples for HIF-alpha expression and VHL genotype, in order to define differentially expressed genes Keywords: Patient Sample Study A total of 57 frozen RCC samples were stained for HIF-1alpha and HIF-2alpha, and genotyped for VHL. 5 VHL WT/HIF-negative, 8 VHL-deficient/HIF-1alpha+/HIF-2alpha+ and 8 VHL-deficient/HIF-2alpha+ tumors were selected for microarray

2008-12-27 | E-GEOD-11904 | biostudies-arrayexpress

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