50 results found
McCracken IR, Saginc G, He L, et al., 2021, Lack of evidence of ACE2 expression and replicative infection by SARSCoV-2 in human endothelial cells, Circulation, ISSN: 0009-7322
Dufton NP, Peghaire CR, Osuna-Almagro L, et al., 2020, Dynamic regulation of canonical TGF beta signalling by endothelial transcription factor ERG protects from liver fibrogenesis (vol 31, pg 450, 2017), NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
Peghaire C, Dufton N, Lang M, et al., 2019, The transcription factor ERG regulates a low shear stress-induced anti-thrombotic pathway in the microvasculature, Nature Communications, Vol: 10, ISSN: 2041-1723
Endothelial cells actively maintain an anti-thrombotic environment; loss of this protective function may lead to thrombosis and systemic coagulopathy. The transcription factor ERG is essential to maintain endothelial homeostasis. Here we show that inducible endothelial ERG deletion (ErgiEC-KO) in mice is associated with spontaneous thrombosis, hemorrhages and systemic coagulopathy. We find that ERG drives transcription of the anti-coagulant thrombomodulin (TM), as shown by reporter assays and chromatin immunoprecipitation. TM expression is regulated by shear stress (SS) via Krüppel-like factor 2 (KLF2). In vitro, ERG regulates TM expression under low SS conditions, by facilitating KLF2 binding to the TM promoter. However, ERG is dispensable for TM expression in high SS conditions. In ErgiEC-KO mice, TM expression is decreased in liver and lung microvasculature exposed to low SS but not in blood vessels exposed to high SS. Our study identifies an endogenous, vascular bed- specific anti-coagulant pathway in microvasculature exposed to low SS.
Garonna E, Botham KM, Birdsey GM, et al., 2019, Vascular Endothelial Growth Factor Receptor-2 Couples Cyclo-Oxygenase-2 with Pro-Angiogenic Actions of Leptin on Human Endothelial Cells (vol 6, e18823, 2011), PLOS ONE, Vol: 14, ISSN: 1932-6203
Kalna V, Yang Y, Peghaire C, et al., 2019, The transcription factor ERG regulates super-enhancers associated with an endothelial-specific gene expression program, Circulation Research, Vol: 124, Pages: 1337-1349, ISSN: 0009-7330
Rationale:The ETS (E-26 transformation-specific) transcription factor ERG (ETS-related gene) is essential for endothelial homeostasis, driving expression of lineage genes and repressing proinflammatory genes. Loss of ERG expression is associated with diseases including atherosclerosis. ERG’s homeostatic function is lineage-specific, because aberrant ERG expression in cancer is oncogenic. The molecular basis for ERG lineage-specific activity is unknown. Transcriptional regulation of lineage specificity is linked to enhancer clusters (super-enhancers).Objective:To investigate whether ERG regulates endothelial-specific gene expression via super-enhancers.Methods and Results:Chromatin immunoprecipitation with high-throughput sequencing in human umbilical vein endothelial cells showed that ERG binds 93% of super-enhancers ranked according to H3K27ac, a mark of active chromatin. These were associated with endothelial genes such as DLL4 (Delta-like protein 4), CLDN5 (claudin-5), VWF (von Willebrand factor), and CDH5 (VE-cadherin). Comparison between human umbilical vein endothelial cell and prostate cancer TMPRSS2 (transmembrane protease, serine-2):ERG fusion-positive human prostate epithelial cancer cell line (VCaP) cells revealed distinctive lineage-specific transcriptome and super-enhancer profiles. At a subset of endothelial super-enhancers (including DLL4 and CLDN5), loss of ERG results in significant reduction in gene expression which correlates with decreased enrichment of H3K27ac and MED (Mediator complex subunit)-1, and reduced recruitment of acetyltransferase p300. At these super-enhancers, co-occupancy of GATA2 (GATA-binding protein 2) and AP-1 (activator protein 1) is significantly lower compared with super-enhancers that remained constant following ERG inhibition. These data suggest distinct mechanisms of super-enhancer regulation in endothelial cells and highlight the unique role of ERG in controlling a core subset of super-enhancers. Most disease-assoc
Dufton NP, peghaire CR, Osuna-Almagro L, et al., 2017, Dynamic regulation of canonical TGFβ signaling by endothelial transcription factor ERG protects from liver fibrogenesis, Nature Communications, Vol: 8, ISSN: 2041-1723
The role of the endothelium in protecting from chronic liver disease and TGFβ-mediated fibrosis remains unclear. Here we describe how the endothelial transcription factor ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGFβ-SMAD signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver fibrogenesis in EC-specific constitutive hemi-deficient (ErgcEC-Het) and inducible homozygous deficient mice (ErgiEC-KO), in a SMAD3-dependent manner. Acute administration of the TNF-α inhibitor etanercept inhibits carbon tetrachloride (CCL4)-induced fibrogenesis in an ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing EndMT in liver disease.
Shah AV, Birdsey GM, Peghaire C, et al., 2017, The endothelial transcription factor ERG mediates Angiopoietin-1-dependent control of Notch signalling and vascular stability, Nature Communications, Vol: 8, ISSN: 2041-1723
Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the transcription factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and β-catenin and is required for Ang1-dependent β-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, β-catenin and Notch signalling to promote vascular stability.
Bauer A, Mylroie H, Thornton C, et al., 2016, Identification of cyclins A1, E1 and vimentin as downstream targets of heme oxygenase-1 in vascular endothelial growth factor-mediated angiogenesis, Scientific Reports, Vol: 6, ISSN: 2045-2322
Angiogenesis is an essential physiological process and an important factor in diseasepathogenesis. However, its exploitation as a clinical target has achieved limited success and novelmolecular targets are required. Although heme oxygenase-1 (HO-1) acts downstream of vascularendothelial growth factor (VEGF) to modulate angiogenesis, knowledge of the mechanismsinvolved remains limited. We set out identify novel HO-1 targets involved in angiogenesis. HO-1depletion attenuated VEGF-induced human endothelial cell (EC) proliferation and tube formation.The latter response suggested a role for HO-1 in EC migration, and indeed HO-1 siRNA negativelyaffected directional migration of EC towards VEGF; a phenotype reversed by HO-1 overexpression.EC from Hmox1-/- mice behaved similarly. Microarray analysis of HO-1-depleted andcontrol EC exposed to VEGF identified cyclins A1 and E1 as HO-1 targets. Migrating HO-1-deficient EC showed increased p27, reduced cyclin A1 and attenuated cyclin-dependent kinase 2activity. In vivo, cyclin A1 siRNA inhibited VEGF-driven angiogenesis, a response reversed by AdHO-1.Proteomics identified structural protein vimentin as an additional VEGF-HO-1 target. HO-1depletion inhibited VEGF-induced calpain activity and vimentin cleavage, while vimentin silencingattenuated HO-1-driven proliferation. Thus, vimentin and cyclins A1 and E1 represent VEGFactivatedHO-1-dependent targets important for VEGF-driven angiogenesis.
Shah AV, Birdsey GM, Randi AM, 2016, Regulation of endothelial homeostasis, vascular development and angiogenesis by the transcription factor ERG, Vascular Pharmacology, Vol: 86, Pages: 3-13, ISSN: 1879-3649
Over the last few years, the ETS transcription factor ERG has emerged as a major regulator ofendothelial function. Multiple studies have shown that ERG plays a crucial role in promotingangiogenesis and vascular stability during development and after birth. In the maturevasculature ERG also functions to maintain endothelial homeostasis, by transactivatinggenes involved in key endothelial functions, whilst repressing expression of pro‐inflammatory genes. Its homeostatic role is lineage-specific, since ectopic expression of ERGin non-endothelial tissues such as prostate is detrimental and contributes to oncogenesis.This review summarises the main roles and pathways controlled by ERG in the vascularendothelium, its transcriptional targets and its functional partners and the emergingevidence on the pathways regulating ERG’s activity and expression.
Thornton CC, Al-Rashed F, Calay D, et al., 2016, Methotrexate-mediated activation of an AMPK-CREB-dependent pathway: a novel mechanism for vascular protection in chronic systemic inflammation, ANNALS OF THE RHEUMATIC DISEASES, Vol: 75, Pages: 439-448, ISSN: 0003-4967
Birdsey GM, Shah AV, Randi AM, 2015, Regulation of vascular development and angiogenesis by the ETS transcription factor ERG, ACTA PHYSIOLOGICA, Vol: 215, Pages: 19-19, ISSN: 1748-1708
Dowsett L, Piper S, Slaviero A, et al., 2015, Endothelial Dimethylarginine Dimethylaminohydrolase 1 Is an Important Regulator of Angiogenesis but Does Not Regulate Vascular Reactivity or Hemodynamic Homeostasis, CIRCULATION, Vol: 131, Pages: 2217-2225, ISSN: 0009-7322
Birdsey GM, Shah AV, Dufton N, et al., 2015, REGULATION OF VASCULAR DEVELOPMENT AND ANGIOGENESIS BY THE TRANSCRIPTION FACTOR ERG, Joint Meeting of the European-Society-for-Microcirculation (ESM) and European-Vascular-Biology-Organisation (EVBO), Publisher: KARGER, Pages: 17-18, ISSN: 1018-1172
Birdsey GM, Shah AV, Dufton N, et al., 2015, The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/β-catenin signaling., Developmental cell, Vol: 32, Pages: 82-96, ISSN: 1534-5807
Blood vessel stability is essential for embryonic development; in the adult, many diseases are associated with loss of vascular integrity. The ETS transcription factor ERG drives expression of VE-cadherin and controls junctional integrity. We show that constitutive endothelial deletion of ERG (Erg(cEC-KO)) in mice causes embryonic lethality with vascular defects. Inducible endothelial deletion of ERG (Erg(iEC-KO)) results in defective physiological and pathological angiogenesis in the postnatal retina and tumors, with decreased vascular stability. ERG controls the Wnt/β-catenin pathway by promoting β-catenin stability, through signals mediated by VE-cadherin and the Wnt receptor Frizzled-4. Wnt signaling is decreased in ERG-deficient endothelial cells; activation of Wnt signaling with lithium chloride, which stabilizes β-catenin levels, corrects vascular defects in Erg(cEC-KO) embryos. Finally, overexpression of ERG in vivo reduces permeability and increases stability of VEGF-induced blood vessels. These data demonstrate that ERG is an essential regulator of angiogenesis and vascular stability through Wnt signaling.
Shah AV, Birdsey GM, Reynolds LE, et al., 2014, The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/beta-catenin signaling, ANGIOGENESIS, Vol: 17, Pages: 715-715, ISSN: 0969-6970
Amsellem V, Dryden NH, Martinelli R, et al., 2014, ICAM-2 regulates vascular permeability and N-cadherin localization through ezrin-radixin-moesin (ERM) proteins and Rac-1 signalling, CELL COMMUNICATION AND SIGNALING, Vol: 12, ISSN: 1478-811X
Birdsey GM, Shah A, Reynolds L, et al., 2014, Regulation of vascular development and angiogenesis by the ETS transcription factor Erg through canonical Wnt signalling, ANGIOGENESIS, Vol: 17, Pages: 276-277, ISSN: 0969-6970
Kostourou V, Lechertier T, Reynolds LE, et al., 2013, FAK-heterozygous mice display enhanced tumour angiogenesis, Nature Communications, Vol: 4, ISSN: 2041-1723
Genetic ablation of endothelial focal adhesion kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularization. Here we show that reduced stromal FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumour growth in vivo. Our results highlight a potential novel role for FAK as a nonlinear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis.
Birdsey GM, Dryden NH, Shah AV, et al., 2012, The transcription factor Erg regulates expression of HDAC6 and multiple pathways involved in endothelial cell migration and angiogenesis, 6th European Meeting on Vascular Biology and Medicine (EMVBM), Publisher: ELSEVIER SCIENCE INC, Pages: 348-349, ISSN: 1537-1891
Bauer A, Thornton CC, Mylroie H, et al., 2012, Investigation of the regulatory role of heme oxygenase-1 and its products in VEGF-mediated angiogenesis, 6th European Meeting on Vascular Biology and Medicine (EMVBM), Publisher: ELSEVIER SCIENCE INC, Pages: 345-345, ISSN: 1537-1891
Dryden NH, Sperone A, Martin-Almedina S, et al., 2012, The Transcription Factor Erg Controls Endothelial Cell Quiescence by Repressing Activity of Nuclear Factor (NF)-kappa B p65, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 287, Pages: 12331-12342
Birdsey GM, Dryden NH, Shah AV, et al., 2012, The transcription factor Erg regulates expression of histone deacetylase 6 and multiple pathways involved in endothelial cell migration and angiogenesis, BLOOD, Vol: 119, Pages: 894-903, ISSN: 0006-4971
Garonna E, Botham KM, Birdsey GM, et al., 2011, Vascular Endothelial Growth Factor Receptor-2 Couples Cyclo-Oxygenase-2 with Pro-Angiogenic Actions of Leptin on Human Endothelial Cells, PLOS ONE, Vol: 6, ISSN: 1932-6203
Sperone A, Dryden NH, Birdsey GM, et al., 2011, The Transcription Factor Erg Inhibits Vascular Inflammation by Repressing NF-kappa B Activation and Proinflammatory Gene Expression in Endothelial Cells, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 31, Pages: 142-150, ISSN: 1079-5642
Sperone A, Dryden N, Birdsey GM, et al., 2010, The transcription factor Erg represses ICAM-1 expression and vascular inflammation, Publisher: ELSEVIER IRELAND LTD, Pages: E17-E17, ISSN: 0021-9150
Sperone A, Birdsey GM, Dryden N, et al., 2010, The Transcription Factor Erg Represses ICAM-1 Expression and Vascular Inflammation, Scientific Sessions on Arteriosclerosis, Thrombosis and Vascular Biology, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: E228-E228, ISSN: 1079-5642
McKinnon TA, Goode EC, Birdsey GM, et al., 2010, Specific N-linked glycosylation sites modulate synthesis and secretion of von Willebrand factor, Blood
Hamdulay SS, Wang B, Birdsey GM, et al., 2010, Celecoxib activates PI-3K/Akt and mitochondrial redox signaling to enhance heme oxygenase-1-mediated anti-inflammatory activity in vascular endothelium, FREE RADICAL BIOLOGY AND MEDICINE, Vol: 48, Pages: 1013-1023, ISSN: 0891-5849
Shovlin CL, Angus G, Manning RA, et al., 2010, Endothelial cell processing and alternatively spliced transcripts of factor VIII: potential implications for coagulation cascades and pulmonary hypertension., PLoS One, Vol: 5
BACKGROUND: Coagulation factor VIII (FVIII) deficiency leads to haemophilia A. Conversely, elevated plasma levels are a strong predictor of recurrent venous thromboemboli and pulmonary hypertension phenotypes in which in situ thromboses are implicated. Extrahepatic sources of plasma FVIII are implicated, but have remained elusive. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemistry of normal human lung tissue, and confocal microscopy, flow cytometry, and ELISA quantification of conditioned media from normal primary endothelial cells were used to examine endothelial expression of FVIII and coexpression with von Willebrand Factor (vWF), which protects secreted FVIII heavy chain from rapid proteloysis. FVIII transcripts predicted from database mining were identified by RT-PCR and sequencing. FVIII mAb-reactive material was demonstrated in CD31+ endothelial cells in normal human lung tissue, and in primary pulmonary artery, pulmonary microvascular, and dermal microvascular endothelial cells. In pulmonary endothelial cells, this protein occasionally colocalized with vWF, centered on Weibel Palade bodies. Pulmonary artery and pulmonary microvascular endothelial cells secreted low levels of FVIII and vWF to conditioned media, and demonstrated cell surface expression of FVIII and vWF Ab-reacting proteins compared to an isotype control. Four endothelial splice isoforms were identified. Two utilize transcription start sites in alternate 5' exons within the int22h-1 repeat responsible for intron 22 inversions in 40% of severe haemophiliacs. A reciprocal relationship between the presence of short isoforms and full-length FVIII transcript suggested potential splice-switching mechanisms. CONCLUSIONS/SIGNIFICANCE: The pulmonary endothelium is confirmed as a site of FVIII secretion, with evidence of synthesis, cell surface expression, and coexpression with vWF. There is complex alternate transcription initiation from the FVIII gene. These findings provide a framework for future re
Randi AM, Sperone A, Dryden NH, et al., 2009, Regulation of angiogenesis by ETS transcription factors, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 37, Pages: 1248-1253, ISSN: 0300-5127
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