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  • Journal article
    Hultman K, Edsfeldt A, Björkbacka H, Dunér P, Sundius L, Nitulescu M, Persson A, Boyle JJ, Nilsson J, Hultgårdh-Nilsson A, Bengtsson E, Gonçalves Iet al., 2019,

    Cartilage oligomeric matrix protein associates with a vulnerable plaque phenotype in human atherosclerotic plaques

    , Stroke, Vol: 50, ISSN: 0039-2499

    Background and Purpose- Extracellular matrix proteins are important in atherosclerotic disease by influencing plaque stability and cellular behavior but also by regulating inflammation. COMP (cartilage oligomeric matrix protein) is present in healthy human arteries and expressed by smooth muscle cells. A recent study showed that transplantation of COMP-deficient bone marrow to apoE-/- mice increased atherosclerotic plaque formation, indicating a role for COMP also in bone marrow-derived cells. Despite the evidence of a role for COMP in murine atherosclerosis, knowledge is lacking about the role of COMP in human atherosclerotic disease. Methods- In the present study, we investigated if COMP was associated with a stable or a vulnerable human atherosclerotic plaque phenotype by analyzing 211 carotid plaques for COMP expression using immunohistochemistry. Results- Plaque area that stained positive for COMP was significantly larger in atherosclerotic plaques associated with symptoms (n=110) compared with asymptomatic plaques (n=101; 9.7% [4.7-14.3] versus 5.6% [2.8-9.8]; P=0.0002). COMP was positively associated with plaque lipids (r=0.32; P=0.000002) and CD68 cells (r=0.15; P=0.036) but was negatively associated with collagen (r=-0.16; P=0.024), elastin (r=-0.14; P=0.041), and smooth muscle cells (r=-0.25; P=0.0002). COMP was positively associated with CD163 (r=0.37; P=0.00000006), a scavenger receptor for hemoglobin/haptoglobin and a marker of Mhem macrophages, and with intraplaque hemorrhage, measured as glycophorin A staining (r=0.28; P=0.00006). Conclusions- The present study shows that COMP is associated to symptomatic carotid atherosclerosis, CD163-expressing cells, and a vulnerable atherosclerotic plaque phenotype in humans.
  • Journal article
    Peghaire C, Dufton N, Lang M, Salles I, Ahnstroem J, Kalna V, Raimondi C, Pericleous C, Inuabasi L, Kiseleva R, Muzykantov V, Mason J, Birdsey G, Randi Aet 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.
  • Journal article
    Smadja DM, Melero-Martin JM, Eikenboom J, Bowman M, Sabatier F, Randi AMet al., 2019,

    Standardization of methods to quantify and culture endothelial colony-forming cells derived from peripheral blood Position paper from the International Society on Thrombosis and Haemostasis SSC

    , JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 17, Pages: 1190-1194, ISSN: 1538-7933
  • Journal article
    Ishihara J, Ishihara A, Starke RD, Peghaire CR, Smith KE, McKinnon TAJ, Tabata Y, Sasaki K, White MJV, Fukunaga K, Laffan MA, Lutolf MP, Randi AM, Hubbell JAet al., 2019,

    The heparin binding domain of von Willebrand factor binds to growth factors and promotes angiogenesis in wound healing

    , BLOOD, Vol: 133, Pages: 2559-2569, ISSN: 0006-4971
  • Journal article
    Kalna V, Yang Y, Peghaire C, Frudd K, hannah R, Shah A, Osuna Almagro L, Boyle J, gottgens B, Ferrer J, Randi A, Birdsey Get 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
  • Journal article
    Issitt T, Bosseboeuf E, De Winter N, Dufton N, Gestri G, Senatore V, Chikh A, Randi AM, Raimondi Cet al., 2019,

    Neuropilin-1 controls endothelial homeostasis by regulating mitochondrial function and iron-dependent oxidative stress via ABCB8

    , iScience, Vol: 11, Pages: 205-223, ISSN: 2589-0042

    The transmembrane protein Neuropilin-1 (NRP1) promotes vascular endothelial growth factor (VEGF) and extracellular matrix signalling in endothelial cells (ECs). Although it is established that NRP1 is essential for angiogenesis, little is known about its role in EC homeostasis. Here, we report that NRP1 promotes mitochondrial function in ECs by preventing iron accumulation and iron-induced oxidative stress through a VEGF-independent mechanism in non-angiogenic ECs. Furthermore, NRP1-deficient ECs have reduced growth and show the hallmarks of cellular senescence. We show that a subcellular pool of NRP1 localises in mitochondria and interacts with the mitochondrial transporter ATP-binding-cassette-B8 (ABCB8). NRP1 loss reduces ABCB8 levels, resulting in iron accumulation, iron-induced mitochondrial superoxide production and iron-dependent EC senescence. Treatment of NRP1-deficient ECs with the mitochondria-targeted antioxidant compound mitoTEMPO or with the iron chelator deferoxamine restores mitochondrial activity, inhibits superoxide production and protects from cellular senescence. This finding identifies an unexpected role of NRP1 in EC homeostasis.
  • Journal article
    Tombetti E, Godi C, Ambrosi A, Doyle F, Jacobs A, Kiprianos AP, Youngstein T, Bechman K, Manfredi AA, Ariff B, Mason Jet al., 2018,

    Novel angiographic scores for evaluation of large vessel vasculitis

    , Scientific Reports, Vol: 8, ISSN: 2045-2322

    Arterial involvement is the cardinal feature of large-vessel vasculitis (LVV) and prevention of disease progression is the principal therapeutic goal. However, development of tools for its evaluation represents a major unmet need. To address this, a widely-applicable imaging tool for LVV, analysing arterial involvement in 17 arterial territories, has been developed and validated. Individual stenosis and dilation scores were generated and combined in a composite score. The methodology was validated cross-sectionally and longitudinally in 131 patients, 96 Takayasu arteritis (TA), 35 large-vessel giant-cell arteritis (LV-GCA). In total, 4420 arterial segments from 260 imaging studies were evaluated. The new scores allowed quantitative grading of LVV arterial involvement with high consistency, revealing inter-patient differences. TA had higher stenosis and composite scores and lower dilation scores than LV-GCA. Baseline stenotic and composite scores reflected arterial damage rather than disease-activity. Longitudinal changes in all three scores correlated with disease activity and mirrored arterial disease evolution, reflecting both progressive injury and lesion improvement. Increases ≥1 in any score were specific for arterial disease progression. The scores objectively quantify arterial involvement in LVV, providing precise definition of disease phenotype and evolution. We propose that they represent novel vascular outcome measures essential for future clinical trials.
  • Journal article
    Dufton NP, peghaire CR, Osuna-Almagro L, Raimondi C, Kalna V, Chuahan A, Webb G, Yang Y, Birdsey GM, Lalor P, Mason JC, Adams D, Randi AMet 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.
  • Journal article
    Boother EJ, Brownlow S, Tighe HC, Bamford KB, Jackson JE, Shovlin CLet al., 2017,

    Cerebral abscess associated with odontogenic bacteremias, hypoxemia, and iron loading in immunocompetent patients with right-to-left shunting through pulmonary arteriovenous malformations.

    , Clinical Infectious Diseases, Vol: 65, Pages: 595-603, ISSN: 1537-6591

    Background: Cerebral abscess is a recognised complication of pulmonary arteriovenous malformations (PAVMs) that allow systemic venous blood to bypass the pulmonary capillary bed through anatomic right-to-left shunts. Broader implications and mechanisms remain poorly explored. Methods: Between June 2005 and December 2016, at a single institution, 445 consecutive adult patients with CT-scan confirmed PAVMs (including 403 (90.5%) with hereditary haemorrhagic telangiectasia) were recruited to a prospective series. Multivariate logistic regression, and detailed peri-abscess histories were evaluated to identify potential associations with cerebral abscess. Rates were compared to an earlier non-overlapping series. Results: Thirty-seven (8.3%) of the 445 patients experienced a cerebral abscesses at median age 50 (range 19-76) years. The rate adjusted for ascertainment bias was 27/435 (6.2%). 29/37 (78.4%) abscess patients had no PAVM diagnosis prior to their abscess, a rate unchanged from earlier UK series. 21/37 (56.7%) suffered residual neurological deficits, most commonly memory/cognition impairment; hemiparesis, and visual defects. Isolation of periodontal microbes, and precipitating dental and other interventional events emphasised potential sources of endovascular inoculations. In multivariate logistic regression, cerebral abscess was associated with low oxygen saturation (indicating greater right-to-left shunting); higher transferrin iron saturation index; intravenous iron use for anemia (adjusted odds ratio 5.4 [95% confidence intervals 1.4, 21.1]); male gender; and venous thromboemboli. There were no relationships with anatomic attributes of PAVMs, or red cell indices often increased due to secondary polycythemia. Conclusions: Greater appreciation of the risk of cerebral abscess in undiagnosed PAVMs is required. Lower SaO2 and intravenous iron may be modifiable risk factors.
  • Journal article
    Medina RJ, Barber CL, Sabatier F, Dignat-George F, Melero-Martin JM, Khosrotehrani K, Ohneda O, Randi AM, Chan JKY, Yamaguchi T, Van Hinsbergh VWM, Yoder MC, Stitt AWet al., 2017,

    Endothelial Progenitors: A Consensus Statement on Nomenclature

    , Stem Cells Translational Medicine, Vol: 6, Pages: 1316-1320, ISSN: 2157-6564

    Endothelial progenitor cell (EPC) nomenclature remains ambiguous and there is a general lack of concordance in the stem cell fieldwith many distinct cell subtypes continually grouped under the term “EPC.” It would be highly advantageous to agree on standards toconfirm an endothelial progenitor phenotype and this should include detailed immunophenotyping, potency assays, and clear separationfrom hematopoietic angiogenic cells which are not endothelial progenitors. In this review, we seek to discourage the indiscriminateuse of “EPCs,” and instead propose precise terminology based on defining cellular phenotype and function. Endothelial colonyforming cells and myeloid angiogenic cells are examples of two distinct and well-defined cell types that have been considered EPCsbecause they both promote vascular repair, albeit by completely different mechanisms of action. It is acknowledged that scientificnomenclature should be a dynamic process driven by technological and conceptual advances; ergo the ongoing “EPC” nomenclatureought not to be permanent and should become more precise in the light of strong scientific evidence. This is especially important asthese cells become recognized for their role in vascular repair in health and disease and, in some cases, progress toward use in celltherapy.
  • Journal article
    Youngstein T, Tombetti E, Mukherjee J, Barwick TD, Al-Nahhas A, Humphreys E, Nash J, Andrews J, Incerti E, Tombolini E, Salerno A, Sartorelli S, Ramirez GA, Papa M, Sabbadini MG, Gianolli L, De Cobelli F, Fallanca F, Baldissera E, Manfredi AA, Picchio M, Mason JCet al., 2017,

    FDG uptake by prosthetic arterial grafts in large vessel vasculitis Is not specific for active disease

    , JACC: Cardiovascular Imaging, Vol: 10, Pages: 1042-1052, ISSN: 1936-878X

    OBJECTIVES: This study investigated the incidence and clinical significance of arterial graft-associated uptake of fluorodeoxyglucose in large-vessel vasculitis (LVV). BACKGROUND: The role of (18)F-labeled fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) in the management of LVV remains to be defined. Although [(18)F]FDG uptake at arterial graft sites raises concerns regarding active arteritis or infection, its clinical significance in LVV has never been formally studied. METHODS: An observational prospective study sought to identify patients with Takayasu arteritis (TA) undergoing [(18)F]FDG-PET/CT more than 6 months after graft surgery from a large cohort of patients from 2 tertiary referral centers. [(18)F]FDG uptake by the graft and native arteries was scored on a scale of 0 to 3 relative to hepatic uptake, and periprosthetic maximum standardized uptake value (SUVmax) was calculated. Periprosthetic [(18)F]FDG uptake in active disease was compared with that in inactive disease, and arterial progression was assessed by prospective magnetic resonance angiography (MRA). RESULTS: Twenty-six subjects with TA were enrolled. All were afebrile with negative blood culture. Periprosthetic uptake was significant in 23 of 26 patients, and the mean SUVmax was 4.21 ± 1.46. Median periprosthetic [(18)F]FDG uptake score (3; interquartile range [IQR]: 3 to 3) was higher than in native aorta (1; IQR: 0 to 1; p < 0.001). Graft-specific [(18)F]FDG uptake was unrelated to disease activity. Despite the high frequency of graft-associated [(18)F]FDG uptake, sequential MRAs did not reveal arterial progression in 25 of 26 patients; the 1 remaining case showed minor progression limited to native arteries. Nine patients underwent repeated PET/CT scanning without showing changes in graft-specific uptake, despite increased treatment. CONCLUSIONS: Significant [(18)F]FDG uptake that is confined to arterial graft sites in patients w
  • Journal article
    Khan E, Ambrose N, Ahnstrom J, Kiprianos A, Stanford M, Eleftheriou D, Brogan P, Mason J, Johns M, Laffan M, Haskard Det al., 2016,

    A low balance between microparticles expressing tissue factor pathway inhibitor and tissue factor is associated with thrombosis in Behçet’s Syndrome

    , Clinical and Experimental Rheumatology, Vol: 6, ISSN: 1593-098X

    Thrombosis is common in Behçet’s Syndrome (BS), and there is a need for better biomarkers for risk assessment. As microparticles expressing Tissue Factor (TF) can contribute to thrombosis in preclinical models, we investigated whether plasma microparticles expressing Tissue Factor (TF) are increased in BS. We compared blood plasma from 72 healthy controls with that from 88 BS patients (21 with a history of thrombosis (Th+) and 67 without (Th−). Using flow cytometry, we found that the total plasma MP numbers were increased in BS compared to HC, as were MPs expressing TF and Tissue Factor Pathway Inhibitor (TFPI) (all p < 0.0001). Amongst BS patients, the Th+ group had increased total and TF positive MP numbers (both p ≤ 0.0002) compared to the Th- group, but had a lower proportion of TFPI positive MPs (p < 0.05). Consequently, the ratio of TFPI positive to TF positive MP counts (TFPI/TF) was significantly lower in Th+ versus Th− BS patients (p = 0.0002), and no patient with a TFPI/TF MP ratio >0.7 had a history of clinical thrombosis. We conclude that TF-expressing MP are increased in BS and that an imbalance between microparticulate TF and TFPI may predispose to thrombosis.
  • Journal article
    Bauer A, Mylroie H, Thornton C, Calay D, Birdsey G, Kiprianos A, Wilson GK, Soares MP, Yin X, Mayr M, Randi A, Mason JCet 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.
  • Journal article
    Khamis RY, Hughes AD, Caga-Anan M, Chang CL, Boyle JJ, Kojima C, Welsh P, Sattar N, Johns M, Sever P, Mayet J, Haskard DOet al., 2016,

    High serum immunoglobulin G and M levels predict freedom from adverse cardiovascular events in hypertension: a nested case-control substudy of the Anglo-Scandinavian Cardiac Outcomes Trial

    , EBioMedicine, Vol: 9, Pages: 372-380, ISSN: 2352-3964

    Aims: We aimed to determine whether the levels of total serum IgM and IgG, together with specific antibodies against malondialdehyde-conjugated low-density lipoprotein (MDA-LDL),can improve cardiovascular risk discrimination.Methods and Results: The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized 9098 patients in the UK and Ireland into the Blood Pressure-Lowering Arm. 485 patients that had cardiovascular (CV) events over 5.5 years were age and sex matched with 1367 controls. Higher baseline total serum IgG, and to a lesser extent IgM, were associated with decreased risk of CV events (IgG odds ratio (OR) per one standard deviation (SD) 0.80[95% confidence interval, CI 0.72,0.89], p<0.0001; IgM 0.83[0.75,0.93], p=0.001), and particularly events due to coronary heart disease (CHD) (IgG OR 0.66 (0.57,0.76); p<0.0001, IgM OR 0.81 (0.71,0.93); p=0.002). The association persisted after adjustment for a basic model with variables in the Framingham Risk Score (FRS) as well as following inclusion of C-reactive protein (CRP) and N-terminal pro-B-type natriuretic peptide (NtProBNP). IgG and IgM antibodies against MDA-LDL were also associated with CV events but their significance was lost following adjustment for total serum IgG and IgM respectively. The area under the receiver operator curve for CV events was improved from the basic risk model when adding in total serum IgG, and there was improvement in continuous and categorical net reclassification(17.6% and 7.5% respectively) as well as in the integrated discrimination index.Conclusion: High total serum IgG levels are an independent predictor of freedom from adverse cardiovascular events, particularly those attributed to CHD, in patients with hypertension.
  • Journal article
    Thornton CC, Al-Rashed F, Calay D, Birdsey GM, Bauer A, Mylroie H, Morley BJ, Randi AM, Haskard DO, Boyle JJ, Mason JCet 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
  • Journal article
    Mylroie H, Dumont O, Bauer A, Thornton CC, Mackey J, Calay D, Hamdulay SS, Choo JR, Boyle JJ, Samarel AM, Randi AM, Evans PC, Mason JCet al., 2015,

    PKC epsilon-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis

    , CARDIOVASCULAR RESEARCH, Vol: 106, Pages: 509-519, ISSN: 0008-6363
  • Journal article
    Lightman S, Taylor SRJ, Bunce C, Longhurst H, Lynn W, Moots R, Stanford M, Tomkins-Netzer O, Yang D, Calder VL, Haskard DOet al., 2015,

    Pegylated interferon-alpha-2b reduces corticosteroid requirement in patients with Behcet's disease with upregulation of circulating regulatory T cells and reduction of Th17

    , ANNALS OF THE RHEUMATIC DISEASES, Vol: 74, Pages: 1138-1144, ISSN: 0003-4967
  • Journal article
    Birdsey GM, Shah AV, Dufton N, Reynolds LE, Osuna Almagro L, Yang Y, Aspalter IM, Khan ST, Mason JC, Dejana E, Göttgens B, Hodivala-Dilke K, Gerhardt H, Adams RH, Randi AMet 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.
  • Journal article
    Iqbal MB, Johns M, Cao J, Liu Y, Yu S-C, Hyde GD, Laffan MA, Marchese FP, Cho SH, Clark AR, Gavins FN, Woollard KJ, Blackshear PJ, Mackman N, Dean JL, Boothby M, Haskard DOet al., 2014,

    PARP-14 combines with tristetraprolin in the selective posttranscriptional control of macrophage tissue factor expression

    , BLOOD, Vol: 124, Pages: 3646-3655, ISSN: 0006-4971
  • Journal article
    Shah AV, Birdsey GM, Reynolds LE, Dufton N, Almagro LO, Yang Y, Aspalter IM, Khan ST, Mason JC, Dejana E, Goettgens B, Hodivala-Dilke K, Gerhardt H, Adams RH, Randi AMet 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

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