Publications
111 results found
Birdsey GM, Shah A, Reynolds L, et al., 2014, Regulation of vascular development and angiogenesis by the ETS transcription factor Erg through canonical Wnt signalling, ANGIOGENESIS, Vol: 17, Pages: 276-277, ISSN: 0969-6970
Paschalaki KE, Starke RD, Hu Y, et al., 2013, Dysfunction of endothelial progenitor cells from smokers and chronic obstructive pulmonary disease patients due to increased DNA damage and senescence, Stem Cells, Vol: 31, Pages: 2813-2826, ISSN: 1066-5099
Cardiovascular disease (CVD) is a major cause of death in smokers, particularly in those with chronic obstructive pulmonary disease (COPD). Circulating endothelial progenitor cells (EPC) are required for endothelial homeostasis, and their dysfunction contributes to CVD. To investigate EPC dysfunction in smokers, we isolated and expanded blood outgrowth endothelial cells (BOEC) from peripheral blood samples from healthy nonsmokers, healthy smokers, and COPD patients. BOEC from smokers and COPD patients showed increased DNA double‐strand breaks and senescence compared to nonsmokers. Senescence negatively correlated with the expression and activity of sirtuin‐1 (SIRT1), a protein deacetylase that protects against DNA damage and cellular senescence. Inhibition of DNA damage response by silencing of ataxia telangiectasia mutated (ATM) kinase resulted in upregulation of SIRT1 expression and decreased senescence. Treatment of BOEC from COPD patients with the SIRT1 activator resveratrol or an ATM inhibitor (KU‐55933) also rescued the senescent phenotype. Using an in vivo mouse model of angiogenesis, we demonstrated that senescent BOEC from COPD patients are dysfunctional, displaying impaired angiogenic ability and increased apoptosis compared to cells from healthy nonsmokers. Therefore, this study identifies epigenetic regulation of DNA damage and senescence as pathogenetic mechanisms linked to endothelial progenitors' dysfunction in smokers and COPD patients. These defects may contribute to vascular disease and cardiovascular events in smokers and could therefore constitute therapeutic targets for intervention.
Randi AM, Laffan MA, Starke RD, 2013, Von Willebrand factor, angiodysplasia and angiogenesis, Mediterranean Journal of Hematology and Infectious Diseases, Vol: 5, ISSN: 2035-3006
The large multimeric glycoprotein Von Willebrand factor (VWF) is best known for its role in haemostasis; however in recent years other functions of VWF have been identified, indicating that this protein is involved in multiple vascular processes. We recently described a new role for VWF in controlling angiogenesis, which may have significant clinical implications for patients with Von Willebrand disease (VWD), a genetic or acquired condition caused by the deficiency or dysfunction of VWF. VWD can be associated with angiodysplasia, a condition of degenerative blood vessels often present in the gastrointestinal tract, linked to dysregulated angiogenesis. Angiodysplasia can cause severe intractable bleeding, often refractory to conventional VWD treatments. In this review we summarise the evidence showing that VWF controls angiogenesis, and review the angiogenic pathways which have been implicated in this process. We discuss the possible mechanisms though which VWF regulates angiopoietin-2 (Ang-2) and integrin αvβ3, leading to signalling through vascular endothelial growth factor receptor-2 (VEGFR2), one of the most potent activators of angiogenesis. We also review the evidence that links VWF with angiodysplasia, and how the newly identified function of VWF in controlling angiogenesis may pave the way for the development of novel therapies for the treatment of angiodysplasia in congenital VWD and in acquired conditions such as Heyde syndrome.
Paschalaki KE, Starke RD, Hu Y, et al., 2013, Endothelial progenitor cells are dysfunctional in smokers and COPD patients due to increased DNA damage and senescence, EUROPEAN RESPIRATORY JOURNAL, Vol: 42, ISSN: 0903-1936
Starke RD, Paschalaki KE, Dyer CEF, et al., 2013, Defective angiopoietin-2 release from von Willebrand disease patients' blood outgrowth endothelial cells, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 11, Pages: 175-175, ISSN: 1538-7933
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- Citations: 3
Starke RD, Chillo O, Pagel J, et al., 2013, Cardiovascular Disease, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 11, Pages: 1-1, ISSN: 1538-7933
Mangles SE, Paschalaki KE, Starke RD, et al., 2013, Increased fibrinolysis on blood outgrowth endothelial cells (BOEC) from chronic thromboembolic pulmonary hypertension (CTEPH) patients, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 11, Pages: 920-921, ISSN: 1538-7933
Kostourou V, Lechertier T, Reynolds LE, et al., 2013, FAK-heterozygous mice display enhanced tumour angiogenesis, Nature Communications, Vol: 4, ISSN: 2041-1723
Genetic ablation of endothelial focal adhesion kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularization. Here we show that reduced stromal FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumour growth in vivo. Our results highlight a potential novel role for FAK as a nonlinear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis.
Starke R, Paschalaki K, Dyer C, et al., 2013, DEFECTIVE VON WILLEBRAND FACTOR AND ANGIOPOIETIN-2 RELEASE FROM VON WILLEBRAND DISEASE PATIENTS' BLOOD OUTGROWTH ENDOTHELIAL CELLS, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A106-A106, ISSN: 1355-6037
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- Citations: 1
Starke RD, Paschalaki KE, Dyer CEF, et al., 2013, Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells, BLOOD, Vol: 121, Pages: 2773-2784, ISSN: 0006-4971
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- Citations: 69
Starke RD, Paschalaki KE, Dyer CE, et al., 2013, Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells, Blood, Vol: 121, Pages: 2773-2784
Von Willebrand disease (VWD) is a heterogeneous bleeding disorder caused by decrease or dysfunction of von Willebrand factor (VWF). A wide range of mutations in the VWF gene have been characterized; however, their cellular consequences are still poorly understood. Here we have used a recently developed approach to study the molecular and cellular basis of VWD. We isolated blood outgrowth endothelial cells (BOECs) from peripheral blood of 4 type 1 VWD and 4 type 2 VWD patients and 9 healthy controls. We confirmed the endothelial lineage of BOECs, then measured VWF messenger RNA (mRNA) and protein levels (before and after stimulation) and VWF multimers. Decreased mRNA levels were predictive of plasma VWF levels in type 1 VWD, confirming a defect in VWF synthesis. However, BOECs from this group of patients also showed defects in processing, storage, and/or secretion of VWF. Levels of VWF mRNA and protein were normal in BOECs from 3 type 2 VWD patients, supporting the dysfunctional VWF model. However, 1 type 2M patient showed decreased VWF synthesis and storage, indicating a complex cellular defect. These results demonstrate for the first time that isolation of endothelial cells from VWD patients provides novel insight into cellular mechanisms of the disease
Haskard DO, Boyle JJ, Evans PC, et al., 2013, Cytoprotective Signaling and Gene Expression in Endothelial Cells and MacrophagesLessons for Atherosclerosis, MICROCIRCULATION, Vol: 20, Pages: 203-216, ISSN: 1073-9688
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- Citations: 8
Dumont O, Mylroie H, Bauer A, et al., 2012, Protein kinase Cε activity induces anti-inflammatory and anti-apoptotic genes via an ERK1/2-and NF-κB-dependent pathway to enhance vascular protection, BIOCHEMICAL JOURNAL, Vol: 447, Pages: 193-204, ISSN: 0264-6021
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- Citations: 10
Birdsey GM, Dryden NH, Shah AV, et al., 2012, The transcription factor Erg regulates expression of HDAC6 and multiple pathways involved in endothelial cell migration and angiogenesis, 6th European Meeting on Vascular Biology and Medicine (EMVBM), Publisher: ELSEVIER SCIENCE INC, Pages: 348-349, ISSN: 1537-1891
Bauer A, Thornton CC, Mylroie H, et al., 2012, Investigation of the regulatory role of heme oxygenase-1 and its products in VEGF-mediated angiogenesis, 6th European Meeting on Vascular Biology and Medicine (EMVBM), Publisher: ELSEVIER SCIENCE INC, Pages: 345-345, ISSN: 1537-1891
Starke RD, Paschalaki KE, Ferraro F, et al., 2012, Endothelial Von Willebrand factor regulates angiogenesis, 6th European Meeting on Vascular Biology and Medicine (EMVBM), Publisher: ELSEVIER SCIENCE INC, Pages: 318-319, ISSN: 1537-1891
Dryden NH, Sperone A, Martin-Almedina S, et al., 2012, The transcription factor erg controls endothelial cell quiescence by repressing activity of Nuclear Factor (NF)-kappa B p65, Journal of Biological Chemistry, Vol: 287, Pages: 12331-12342, ISSN: 0021-9258
The interaction of transcription factors with specific DNA sequences is critical for activation of gene expression programs. In endothelial cells (EC), the transcription factor NF-κB is important in the switch from quiescence to activation, and is tightly controlled to avoid excessive inflammation and organ damage. Here we describe a novel mechanism that controls the activation of NF-κB in EC. The transcription factor Erg, the most highly expressed ETS member in resting EC, controls quiescence by repressing proinflammatory gene expression. Focusing on intercellular adhesion molecule 1(ICAM)-1 as a model, we identify two ETS binding sites (EBS −118 and −181) within the ICAM-1 promoter required for Erg-mediated repression. We show that Erg binds to both EBS −118 and EBS −181, the latter located within the NF-κB binding site. Interestingly, inhibition of Erg expression in quiescent EC results in increased NF-κB-dependent ICAM-1 expression, indicating that Erg represses basal NF-κB activity. Erg prevents NF-κB p65 from binding to the ICAM-1 promoter, suggesting a direct mechanism of interference. Gene set enrichment analysis of transcriptome profiles of Erg and NF-κB-dependent genes, together with chromatin immunoprecipitation (ChIP) studies, reveals that this mechanism is common to other proinflammatory genes, including cIAP-2 and IL-8. These results identify a role for Erg as a gatekeeper controlling vascular inflammation, thus providing an important barrier to protect against inappropriate endothelial activation.
Randi AM, 2012, VWF, angiodysplasia and endothelial progenitor cells: novel insights from basic science, HAEMOPHILIA, Vol: 18, Pages: 9-9, ISSN: 1351-8216
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- Citations: 1
Birdsey GM, Dryden NH, Shah AV, et al., 2012, The transcription factor Erg regulates expression of histone deacetylase 6 and multiple pathways involved in endothelial cell migration and angiogenesis, BLOOD, Vol: 119, Pages: 894-903, ISSN: 0006-4971
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- Citations: 57
Mckinnon TAJ, Starke RD, Ediriwickrema K, et al., 2011, Von Willebrand Factor Binds to the Endothelial Growth Factor Angiopoietin-2 Both within Endothelial Cells and Upon Release From Weibel Palade Bodies, 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH)/Symposium on the Basic Science of Hemostasis and Thrombosis, Publisher: AMER SOC HEMATOLOGY, Pages: 319-319, ISSN: 0006-4971
Starke RD, Paschalaki KE, Ferraro F, et al., 2011, BLOOD-DERIVED ENDOTHELIAL PROGENITOR CELLS FROM VON WILLEBRAND'S DISEASE PATIENTS DEMONSTRATE THAT VON WILLEBRAND FACTOR REGULATES ANGIOGENESIS, Publisher: B M J PUBLISHING GROUP, Pages: 14-14, ISSN: 1355-6037
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- Citations: 1
Paschalaki K, Starke RD, Mercado N, et al., 2011, ENDOTHELIAL COLONY FORMING CELLS (ECFC) ARE SENESCENT AND DYSFUNCTIONAL IN COPD DUE TO REDUCED SIRTUIN-1 LEVELS, Publisher: B M J PUBLISHING GROUP, Pages: 20-20, ISSN: 1355-6037
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- Citations: 5
Garonna E, Botham KM, Birdsey GM, et al., 2011, Vascular Endothelial Growth Factor Receptor-2 Couples Cyclo-Oxygenase-2 with Pro-Angiogenic Actions of Leptin on Human Endothelial Cells, PLOS ONE, Vol: 6, ISSN: 1932-6203
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- Citations: 81
Starke RD, Ferraro F, Paschalaki KE, et al., 2011, Endothelial von Willebrand factor regulates angiogenesis, BLOOD, Vol: 117, Pages: 1071-1080, ISSN: 0006-4971
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- Citations: 358
Sperone A, Dryden NH, Birdsey GM, et al., 2011, The Transcription Factor Erg Inhibits Vascular Inflammation by Repressing NF-κB Activation and Proinflammatory Gene Expression in Endothelial Cells, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 31, Pages: 142-150, ISSN: 1079-5642
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- Citations: 50
Sperone A, Birdsey GM, Dryden N, et al., 2010, The Transcription Factor Erg Represses ICAM-1 Expression and Vascular Inflammation, Scientific Sessions on Arteriosclerosis, Thrombosis and Vascular Biology, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: E228-E228, ISSN: 1079-5642
Ali F, Ali NS, Bauer A, et al., 2010, PPARδ and PGC1α act cooperatively to induce haem oxygenase-1 and enhance vascular endothelial cell resistance to stress, CARDIOVASCULAR RESEARCH, Vol: 85, Pages: 701-710, ISSN: 0008-6363
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- Citations: 49
Randi AM, Sperone A, Dryden NH, et al., 2009, Regulation of angiogenesis by ETS transcription factors, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 37, Pages: 1248-1253, ISSN: 0300-5127
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- Citations: 59
Randi AM, Bussolati B, 2009, Myeloid cell-induced angiogenesis: a sticky business, BLOOD, Vol: 113, Pages: 6508-6510, ISSN: 0006-4971
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- Citations: 3
Birdsey GM, Dryden NH, Arnsellem V, et al., 2008, The transcription factor Erg regulates angiogenesis and endothelial apoptosis through VE-cadherin, Spring Meeting of the British-Atherosclerosis-Society on Angiogenesis and Atherosclerosis, Publisher: ELSEVIER IRELAND LTD, Pages: 465-465, ISSN: 0021-9150
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