Publications
111 results found
Randi AM, 2017, Angiogenesis and the ADAMTS13-VWF balance, BLOOD, Vol: 130, Pages: 1-2, ISSN: 0006-4971
Medina RJ, Barber CL, Sabatier F, et 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.
Randi AM, Laffan MA, 2017, Von Willebrand factor and angiogenesis: basic and applied issues, Journal of Thrombosis and Haemostasis, Vol: 15, Pages: 13-20, ISSN: 1538-7933
The recent discovery that von Willebrand factor (VWF) regulates blood vessel formation has opened a novel perspective on the function of this complex protein. VWF was discovered as a key component of haemostasis, capturing platelets at sites of endothelial damage and synthesized in megakaryocytes and endothelial cells (EC). In recent years, novel functions and binding partners have been identified for VWF. The finding that loss of VWF in EC results in enhanced, possibly dysfunctional angiogenesis is consistent with the clinical observations that in some patients with Von Willebrand disease (VWD), vascular malformations can cause severe gastrointestinal (GI) bleeding. In vitro and in vivo studies indicate that VWF can regulate angiogenesis through multiple pathways, both intracellular and extracellular, although their relative importance is still unclear. Investigation of these pathways has been greatly facilitated by the ability to isolate EC from progenitors circulating in the peripheral blood of normal controls and patients with VWD. In the next few years, these will yield further evidence on the molecular pathways controlled by VWF and shed light on this novel and fascinating area of vascular biology. In this article, we will review the evidence supporting a role for VWF in blood vessel formation, the link between VWF dysfunction and vascular malformations causing GI bleeding and how they may be causally related. Finally, we will discuss how these findings point to novel therapeutic approaches to bleeding refractory to VWF replacement therapy in VWD.
Shah A, Birdsey G, Peghaire C, et al., 2017, The ETS Transcription Factor ERG regulates Notch Signalling and Controls the Balance of Expression between the Notch Ligands Delta-like ligand 4 and Jagged1, 2nd Joint Meeting of the European-Society-for-Microcirculation (ESM) and European-Vascular-Biology-Organisation (EVBO), Publisher: KARGER, Pages: 46-46, ISSN: 1018-1172
Smith K, Starke R, Dufton N, et al., 2017, Von Willebrand Factor modulates blood vessel formation and function via Angiopoietin-2, 2nd Joint Meeting of the European-Society-for-Microcirculation (ESM) and European-Vascular-Biology-Organisation (EVBO), Publisher: KARGER, Pages: 38-38, ISSN: 1018-1172
Beuerle MG, Dufton NP, Randi AM, et al., 2016, Molecular dynamics studies on the DNA-binding process of ERG, Molecular BioSystems, Vol: 12, Pages: 3600-3610, ISSN: 1742-206X
The ETS family of transcription factors regulate gene targets by binding to a core GGAA DNA-sequence. The ETS factor ERG is required for homeostasis and lineage-specific functions in endothelial cells, some subset of haemopoietic cells and chondrocytes; its ectopic expression is linked to oncogenesis in multiple tissues. To date details of the DNA-binding process of ERG including DNA-sequence recognition outside the core GGAA-sequence are largely unknown. We combined available structural and experimental data to perform molecular dynamics simulations to study the DNA-binding process of ERG. In particular we were able to reproduce the ERG DNA-complex with a DNA-binding simulation starting in an unbound configuration with a final root-mean-square-deviation (RMSD) of 2.1 Å to the core ETS domain DNA-complex crystal structure. This allowed us to elucidate the relevance of amino acids involved in the formation of the ERG DNA-complex and to identify Arg385 as a novel key residue in the DNA-binding process. Moreover we were able to show that water-mediated hydrogen bonds are present between ERG and DNA in our simulations and that those interactions have the potential to achieve sequence recognition outside the GGAA core DNA-sequence. The methodology employed in this study shows the promising capabilities of modern molecular dynamics simulations in the field of protein DNA-interactions.
Dulak J, Alexander MY, Randi AM, 2016, Vascular biology: New mechanisms and pathways, VASCULAR PHARMACOLOGY, Vol: 86, Pages: 1-2, ISSN: 1537-1891
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.
Randi AM, 2016, Endothelial dysfunction in von Willebrand disease: angiogenesis and angiodysplasia, THROMBOSIS RESEARCH, Vol: 141, Pages: S55-S58, ISSN: 0049-3848
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
Aims Premature cardiovascular events complicate chronic inflammatory conditions. Low-dose weekly methotrexate (MTX), the most widely used disease-modifying drug for rheumatoid arthritis (RA), reduces disease-associated cardiovascular mortality. MTX increases intracellular accumulation of adenosine monophosphate (AMP) and 5-aminoimidazole-4-carboxamide ribonucleotide which activates AMP-activated protein kinase (AMPK). We hypothesised that MTX specifically protects the vascular endothelium against inflammatory injury via induction of AMPK-regulated protective genes.Methods/results In the (NZW×BXSB)F1 murine model of inflammatory vasculopathy, MTX 1 mg/kg/week significantly reduced intramyocardial vasculopathy and attenuated end-organ damage. Studies of human umbilical vein endothelial cells (HUVEC) and arterial endothelial cells (HAEC) showed that therapeutically relevant concentrations of MTX phosphorylate AMPKαThr172, and induce cytoprotective genes including manganese superoxide dismutase (MnSOD) and haem oxygenase-1 (HO-1). These responses were preserved when HUVECs were pretreated with tumour necrosis factor-α to mimic dysfunctional endothelium. Furthermore, MTX protected against glucose deprivation-induced endothelial apoptosis. Mechanistically, MTX treatment led to cyclic AMP response element-binding protein (CREB)Ser133 phosphorylation, while AMPK depletion attenuated this response and the induction of MnSOD and HO-1. CREB siRNA inhibited upregulation of both cytoprotective genes by MTX, while chromatin immunoprecipitation demonstrated CREB binding to the MnSOD promoter in MTX-treated EC. Likewise, treatment of (NZW×BXSB)F1 mice with MTX enhanced AMPKαThr172 phosphorylation and MnSOD, and reduced aortic intercellular adhesion molecule-1 expression.Conclusions These data suggest that MTX therapeutically conditions vascular endothelium via activation of AMPK-CREB. We propose that this mechanism contributes to the protection against
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
Tornavaca O, Chia M, Dufton N, et al., 2015, ZO-1 CONTROLS ENDOTHELIAL ADHERENS JUNCTIONS, CELL-CELL TENSION, ANGIOGENESIS AND BARRIER FORMATION, ANTICANCER RESEARCH, Vol: 35, Pages: 4304-4305, ISSN: 0250-7005
Mylroie H, Dumont O, Bauer A, et al., 2015, PKCε-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
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- Citations: 79
Randi A, 2015, The multiple roles of von Willebrand factor: regulation of angiogenesis, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 13, Pages: 22-22, ISSN: 1538-7933
Reed DM, Paschalaki KE, Starke RD, et al., 2015, An autologous endothelial cell: peripheral blood mononuclear cell assay that detects cytokine storm responses to biologics, The FASEB Journal, Vol: 29, Pages: 2595-2602, ISSN: 0892-6638
There is an urgent unmet need for human tissue bioassays to predict cytokine storm responses to biologics. Current bioassays that detect cytokine storm responses in vitro rely on endothelial cells, usually from umbilical veins or cell lines, cocultured with freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy adult volunteers. These assays therefore comprise cells from 2 separate donors and carry the disadvantage of mismatched tissues and lack the advantage of personalized medicine. Current assays also do not fully delineate mild (such as Campath) and severe (such as TGN1412) cytokine storm‐inducing drugs. Here, we report a novel bioassay where endothelial cells grown from stem cells in the peripheral blood (blood outgrowth endothelial cells) and PBMCs from the same donor can be used to create an autologous coculture bioassay that responds by releasing a plethora of cytokines to authentic TGN1412 but only modestly to Campath and not to control antibodies such as Herceptin, Avastin, and Arzerra. This assay performed better than the traditional mixed donor assay in terms of cytokine release to TGN1412 and, thus, we suggest provides significant advancement and a definitive system by which biologics can be tested and paves the way for personalized medicine.—Reed, D. M., Paschalaki, K. E., Starke, R. D., Mohamed, N. A., Sharp, G., Fox, B., Eastwood, D., Bristow, A., Ball, C., Vessillier, S., Hansel, T. T., Thorpe, S. J., Randi, A. M., Stebbings, R., Mitchell, J. A. An autologous endothelial cell:peripheral blood mononuclear cell assay that detects cytokine storm responses to biologics. FASEB J. 29, 2595‐2602 (2015). www.fasebj.org
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
Background—Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthesis and a risk factor for cardiovascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) enzymes are responsible for ADMA breakdown. It has been reported that endothelial DDAH1 accounts for the majority of ADMA metabolism. However, we and others have shown strong DDAH1 expression in a range of nonendothelial cell types, suggesting that the endothelium is not the only site of metabolism. We have developed a new endothelium-specific DDAH1 knockout mouse (DDAH1En−/−) to investigate the significance of endothelial ADMA in cardiovascular homeostasis.Methods and Results—DDAH1 deletion in the DDAH1En−/− mouse was mediated by Tie-2 driven Cre expression. DDAH1 deletion was confirmed through immunocytochemistry, whereas Western blotting showed that DDAH1 remained in the kidney and liver, confirming expression in nonendothelial cells. Plasma ADMA was unchanged in DDAH1En−/− mice, and cultured aortas released amounts of ADMA to similar to controls. Consistent with these observations, vasoreactivity ex vivo and hemodynamics in vivo were unaltered in DDAH1En−/− mice. In contrast, we observed significantly impaired angiogenic responses both ex vivo and in vivo.Conclusions—We demonstrate that endothelial DDAH1 is not a critical determinant of plasma ADMA, vascular reactivity, or hemodynamic homeostasis. DDAH1 is widely expressed in a range of vascular and nonvascular cell types; therefore, the additive effect of DDAH1 expression in multiple organ systems determines plasma ADMA concentrations. Endothelial deletion of DDAH1 profoundly impairs the angiogenic capacity of endothelial cells, indicating that intracellular ADMA is a critical determinant of endothelial cell response.
Starke RD, Chillo O, Smith K, et al., 2015, von Willebrand factor deficiency causes increased angiogenesis following ischemic tissue damage, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 13, Pages: 252-253, ISSN: 1538-7933
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- Citations: 1
Tornavaca O, Chia M, Dufton N, et al., 2015, ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation, JOURNAL OF CELL BIOLOGY, Vol: 208, Pages: 821-838, ISSN: 0021-9525
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- Citations: 341
Birdsey GM, Shah AV, Dufton N, et al., 2015, The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/beta-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 (ErgcEC-KO) in mice causes embryonic lethality with vascular defects. Inducible endothelial deletion of ERG (ErgiEC-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 ErgcEC-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.
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
Smith K, Starke RD, Mckinnon TAJ, et al., 2015, RECIPROCAL REGULATION OF ANGIOPOIETIN 2 & VON WILLEBRAND FACTOR EXPRESSION IN ENDOTHELIAL CELLS, Joint Meeting of the European-Society-for-Microcirculation (ESM) and European-Vascular-Biology-Organisation (EVBO), Publisher: KARGER, Pages: 51-52, ISSN: 1018-1172
Randi AM, 2015, A NEW ROLE FOR VWF IN THE CONTROL OF ANGIOGENESIS, Joint Meeting of the European-Society-for-Microcirculation (ESM) and European-Vascular-Biology-Organisation (EVBO), Publisher: KARGER, Pages: 81-81, ISSN: 1018-1172
Payne L, Bastos B, Haskard D, et al., 2015, NOVEL ENDOTHELIAL ISOFORMS OF THE ETS TRANSCRIPTION FACTOR ERG, Joint Meeting of the European-Society-for-Microcirculation (ESM) and European-Vascular-Biology-Organisation (EVBO), Publisher: KARGER, Pages: 47-47, ISSN: 1018-1172
Shah AV, Birdsey GM, Reynolds LE, et al., 2014, The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/β-catenin signaling, ANGIOGENESIS, Vol: 17, Pages: 715-715, ISSN: 0969-6970
Dufton N, Almagro LO, Birdsey G, et al., 2014, THE ENDOTHELIAL TRANSCRIPTION FACTOR ERG INHIBITS VASCULAR INFLAMMATION, HEART, Vol: 100, Pages: A115-A116, ISSN: 1355-6037
Hamdulay SS, Wang B, Calay D, et al., 2014, Synergistic therapeutic vascular cytoprotection against complement- mediated injury induced via a PKC alpha-, AMPK-, and CREB- dependent pathway, Journal of Immunology, Vol: 192, Pages: 4316-4327, ISSN: 1550-6606
Endothelial injury and dysfunction precede accelerated arterial disease in allograft vasculopathy and systemic autoimmune diseases and involve pathogenic Abs and complement. Recent reports suggest that switching to rapamycin from calcineurin antagonists reduces posttransplant vasculopathy and prolongs survival following cardiac transplantion. The majority of these patients also receive statin therapy. We examined potential mechanisms underlying this protective response in human endothelial cells and identified synergy between rapamycin and atorvastatin. Mechanistically, atorvastatin and rapamycin activated a protein kinase Cα, AMP-activated kinase, and CREB-dependent vasculoprotective pathway, which induced decay-accelerating factor (DAF) promoter activity via binding to the cAMP response element, mutation of which attenuated promoter activity. This response significantly increased endothelial cell surface DAF and enhanced protection against complement-mediated injury. Synergy with rapamycin was reproduced by simvastatin, whereas combining atorvastatin with cyclosporine or mycophenolate in place of rapamycin was ineffective. Importantly, synergy was reproduced in vivo, in which only atorvastatin and rapamycin therapy in combination was sufficient to induce DAF on murine aortic endothelium. We believe this pathway represents an important therapeutically inducible vasculoprotective mechanism for diseases mediated by pathogenic Abs and complement, including posttransplant vasculopathy and systemic lupus erythematosus. Although our study focuses on the vascular endothelium, the findings are likely to be broadly applicable, given the diverse cellular expression of DAF.
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
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- Citations: 18
Dias P, Navaratnarajah M, Alayoubi S, et al., 2014, IVABRADINE ALTERS FIBROBLAST NUMBER AND TRANSFORMING GROWTH FACTOR BETA 1 EXPRESSION IN HEART FAILURE, HEART, Vol: 100, Pages: A4-A4, ISSN: 1355-6037
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Starke RD, Paschalaki K, Millar CM, et al., 2014, Von Willebrand factor (VWF) regulates angiogenesis through angiopoietin-2 (Ang-2)-dependent and independent pathways, ANGIOGENESIS, Vol: 17, Pages: 290-290, ISSN: 0969-6970
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