115 results found
Paschalaki K, Rossios C, Pericleous C, et al., 2022, Inhaled corticosteroids reduce senescence in endothelial progenitor cells from COPD patients, Thorax, ISSN: 0040-6376
Cellular senescence contributes to the pathophysiology of chronic obstructive pulmonarydisease (COPD) and cardiovascular disease. Using endothelial-colony-forming-cells (ECFC),we have demonstrated accelerated senescence in smokers and COPD patients compared tonon-smokers. Subgroup analysis suggests that ECFC from COPD patients on inhaledcorticosteroids (ICS) (n=14; 8 on ICS) exhibited significantly reduced senescence(Senescence-associated-beta galactosidase activity, p21CIP1), markers of DNA damageresponse (DDR) and IFN-γ-inducible-protein-10 compared to COPD patients not on ICS. Invitro studies using human-umbilical-vein-endothelial-cells showed a protective effect of ICSon the DDR, senescence and apoptosis caused by oxidative-stress, suggesting a protectivemolecular mechanism of action of corticosteroids on endothelium.
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, Pages: 1-1, 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, Pages: 1-17, 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.
Lasch M, Kleinert EC, Meister S, et al., 2019, Extracellular RNA released due to shear stress controls natural bypass growth by mediating mechanotransduction in mice, BLOOD, Vol: 134, Pages: 1469-1479, ISSN: 0006-4971
Smadja DM, Melero-Martin JM, Eikenboom J, et 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
Ishihara J, Ishihara A, Starke RD, et 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
During wound healing, the distribution, availability, and signaling of growth factors (GFs) are orchestrated by their binding to extracellular matrix components in the wound microenvironment. Extracellular matrix proteins have been shown to modulate angiogenesis and promote wound healing through GF binding. The hemostatic protein von Willebrand factor (VWF) released by endothelial cells (ECs) in plasma and in the subendothelial matrix has been shown to regulate angiogenesis; this function is relevant to patients in whom VWF deficiency or dysfunction is associated with vascular malformations. Here, we show that VWF deficiency in mice causes delayed wound healing accompanied by decreased angiogenesis and decreased amounts of angiogenic GFs in the wound. We show that in vitro VWF binds to several GFs, including vascular endothelial growth factor-A (VEGF-A) isoforms and platelet-derived growth factor-BB (PDGF-BB), mainly through the heparin-binding domain (HBD) within the VWF A1 domain. VWF also binds to VEGF-A and fibroblast growth factor-2 (FGF-2) in human plasma and colocalizes with VEGF-A in ECs. Incorporation of the VWF A1 HBD into fibrin matrices enables sequestration and slow release of incorporated GFs. In vivo, VWF A1 HBD-functionalized fibrin matrices increased angiogenesis and GF retention in VWF-deficient mice. Treatment of chronic skin wounds in diabetic mice with VEGF-A165 and PDGF-BB incorporated within VWF A1 HBD-functionalized fibrin matrices accelerated wound healing, with increased angiogenesis and smooth muscle cell proliferation. Therefore, the VWF A1 HBD can function as a GF reservoir, leading to effective angiogenesis and tissue regeneration.
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
King O, Kermani F, Wang B, et al., 2019, Endothelial Cell Regulation of Excitation-Contraction Coupling in Induced Pluripotent Stem Cell Derived Myocardium, 63rd Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 153A-153A, ISSN: 0006-3495
Issitt T, Bosseboeuf E, De Winter N, et 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.
Randi AM, 2018, Von Willebrand Factor in Angiogenesis and Angiodysplasia, 60th Annual Meeting of the American-Society-of-Hematology (ASH), Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Paschalaki KE, Randi AM, 2018, Recent advances in endothelial colony forming cells toward their use in clinical translation, Frontiers in Medicine, Vol: 5, ISSN: 2296-858X
The term “Endothelial progenitor cell” (EPC) has been used to describe multiple cell populations that express endothelial surface makers and promote vascularisation. However, the only population that has all the characteristics of a real “EPC” is the Endothelial Colony Forming Cells (ECFC). ECFC possess clonal proliferative potential, display endothelial and not myeloid cell surface markers, and exhibit pronounced postnatal vascularisation ability in vivo. ECFC have been used to investigate endothelial molecular dysfunction in several diseases, as they give access to endothelial cells from patients in a non-invasive way. ECFC also represent a promising tool for revascularization of damaged tissue. Here we review the translational applications of ECFC research. We discuss studies which have used ECFC to investigate molecular endothelial abnormalities in several diseases and review the evidence supporting the use of ECFC for autologous cell therapy, gene therapy and tissue regeneration. Finally, we discuss ways to improve the therapeutic efficacy of ECFC in clinical applications, as well as the challenges that must be overcome to use ECFC in clinical trials for regenerative approaches.
Nowak-Sliwinska P, Alitalo K, Allen E, et al., 2018, Consensus guidelines for the use and interpretation of angiogenesis assays, Angiogenesis, Vol: 21, Pages: 425-532, ISSN: 0969-6970
The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.
Randi AM, Smith KE, Castaman G, 2018, von Willebrand factor regulation of blood vessel formation, Blood, Vol: 132, Pages: 132-140, ISSN: 1528-0020
Several important physiological processes, from permeability to inflammation to haemostasis, take place at the vessel wall and are regulated by endothelial cells (EC). Thus, proteins that have been identified as regulators of one process are increasingly found to be involved in other vascular functions. Such is the case for Von Willebrand Factor (VWF), a large glycoprotein best known for its critical role in haemostasis. In vitro and in vivo studies have shown that lack of VWF causes enhanced vascularisation, both constitutively and following ischemia. This evidence is supported by studies on blood outgrowth endothelial cells (BOEC) from patients with lack of VWF synthesis (type 3 von Willebrand disease [VWD]). The molecular pathways are likely to involve VWF binding partners, such as integrin αvβ3, and components of Weibel Palade bodies (WPB), such as Angiopoietin-2 and Galectin-3, whose storage is regulated by VWF; these converge on the master regulator of angiogenesis and endothelial homeostasis, vascular endothelial growth factor (VEGF) signalling. Recent studies suggest that the roles of VWF may be tissue-specific. The ability of VWF to regulate angiogenesis has clinical implications for a subset of VWD patients with severe, intractable gastrointestinal bleeding due to vascular malformations. In this article, we review the evidence showing that VWF is involved in blood vessel formation, discuss the role of VWF high molecular weight multimers in regulating angiogenesis, and the value of studies on BOEC in developing a precision medicine approach to validate novel treatments for angiodysplasia in congenital VWD and acquired von Willebrand syndrome.
Schmid CD, Schledzewski K, Mogler C, et al., 2018, GPR182 is a novel marker for sinusoidal endothelial differentiation with distinct GPCR signaling activity in vitro, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 497, Pages: 32-38, ISSN: 0006-291X
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, Pages: 1-14, 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.
Perbellini F, Watson SA, Scigliano M, et al., 2017, Investigation of cardiac fibroblasts using myocardial slices, Cardiovascular Research, Vol: 114, Pages: 77-89, ISSN: 1755-3245
AimsCardiac fibroblasts (CFs) are considered the principal regulators of cardiac fibrosis. Factors that influence CF activity are difficult to determine. When isolated and cultured in vitro, CFs undergo rapid phenotypic changes including increased expression of α-SMA. Here we describe a new model to study CFs and their response to pharmacological and mechanical stimuli using in vitro cultured mouse, dog and human myocardial slices.Methods and resultsUnloading of myocardial slices induced CF proliferation without α-SMA expression up to 7 days in culture. CFs migrating onto the culture plastic support or cultured on glass expressed αSMA within 3 days. The cells on the slice remained αSMA(−) despite transforming growth factor-β (20 ng/ml) or angiotensin II (200 µM) stimulation. When diastolic load was applied to myocardial slices using A-shaped stretchers, CF proliferation was significantly prevented at Days 3 and 7 (P < 0.001).ConclusionsMyocardial slices allow the study of CFs in a multicellular environment and may be used to effectively study mechanisms of cardiac fibrosis and potential targets.
Paschalaki KE, Zampetaki A, Baker JR, et al., 2017, Downregulation of MicroRNA-126 Augments DNA Damage Response in Cigarette Smokers and COPD Patients., Am J Respir Crit Care Med
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, Pages: 1-16, 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.
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.
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
Yang Y, Kalna V, Shah A, et al., 2017, The transcription factor ERG controls distinct TRANSCRIPTIONAL regulatory programs in the vascular ENDOTHELIUM and in prostate cancer cells, 2nd Joint Meeting of the European-Society-for-Microcirculation (ESM) and European-Vascular-Biology-Organisation (EVBO), Publisher: KARGER, Pages: 58-58, ISSN: 1018-1172
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
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
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