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  • 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
    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
    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
    Khan E, Ambrose N, Ahnstrom J, Kiprianos A, Stanford M, Eleftheriou D, Brogan P, Mason J, Johns M, Laffan M, Haskard D, Khan E, Ambrose NE, Ahnström J, Kiprianos AP, Stanford MR, Eleftheriou D, Brogan PA, Mason JC, Johns M, Laffan MA, Haskard DOet 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
    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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