The focus of the group is to understand the basic mechanisms which regulate endothelial homeostasis.
Endothelial cells (EC) regulate critical vascular functions, such as traffic of cells from blood to tissues, clotting, permeability and angiogenesis. Maintenance of endothelial homeostasis is essential for the prevention and control of many diseases, including vascular inflammatory, thrombotic diseases and atherosclerosis. Recently, a role of endothelial cells in maintaining tissue homeostasis has also been identified, making this area critical for a wide number of diseases and for regenerative medicine approaches.We are interested in the transcriptional and epigenetic pathways which control endothelial homeostasis and how these are disrupted in disease, to develop novel strategies to prevent or treat vascular diseases. A few key transcription factor families control endothelial function; we have focused on the ETS related gene ERG, the most highly expressed ETS transcription factor in healthy endothelial cells. We have shown that ERG is essential for vascular development and angiogenesis, since constitutive endothelial specific deletion of ERG causes embryonic lethality and inducible endothelial specific deletion of ERG causes angiogenesis defects. We have also found that endothelial ERG protects cells from endothelial-to-mesenchymal (EndMT) transition, a process implicated in diseases including atherosclerosis and liver fibrosis. ERG endothelial expression is lost in tissue samples from patients with atherosclerosis and chronic liver fibrosis. Current studies focus on the role of ERG in other fibrotic disease, particularly in the heart. We are also looking at the epigenetic mechanisms that underpin ERG’s function, with a view of applying these discoveries to restore ERG activity in damaged endothelium. ERG is one of a handful of factors required to maintain endothelial lineage identity; genomic studies in the group focus on these pathways, which may provide essential information for the generation of vascular networks for regenerative medicine.Projects on the transcriptional regulation of angiogenesis are being carried out in close collaboration with Dr Graeme Birdsey (lecturer in Vascular Sciences). His group uses in vitro molecular cell biology techniques and in vivo models to study the role of ETS family transcription factors in mediating growth factor signalling to endothelial cells. Recent work from Dr Birdsey’s group has focussed on defining the signalling networks controlled by isoforms of ERG and their role in regulating sprouting angiogenesis. The ultimate aim is to identify novel therapeutic targets for treatment of pathological angiogenesis.
We are also interested in translating our endothelial research in patients; for this reason, we have developed a translational approach, by isolating Blood Outgrowth Endothelial Cells - BOEC (also called Endothelial Colony Forming Cells or ECFC) from blood. We have used these cells to study the endothelial dysfunction found in patients with Von Willebrand Disease (VWD), a common bleeding disorder caused by decrease or dysfunction of Von Willebrand Factor (VWF), a key haemostatic protein. In some of these patients, the bleeding diathesis is made worse by the presence of vascular malformations (Angiodysplasia) in the gastrointestinal (GI) tract, which can cause severe, intractable bleeding requiring frequent transfusions. Our discovery that VWF controls the formation of blood vessels opened the way to a novel concept for the management of these patients. Studies on the pathways controlled by VWF, using in vitro and in vivo models and well as BOEC from VWD patients, will hopefully provide novel therapeutic targets for the management of GI bleeding in VWD.
We have also used BOEC to study patients with chronic obstructive pulmonary disease (COPD), who often present with cardiovascular (CV) complications and develop endothelial dysfunction due to cigarette smoke. We showed that BOEC from these patients retain epigenetic dysfunction, which can be corrected by pharmacological treatment. Ongoing studies aim to define the epigenetic profile of BOEC from healthy controls and CV disease patients. Thus, BOEC can be used to characterize acquired endothelial defects in patients, which may identify novel candidate for biomarkers of disease and to develop precision medicine approaches.
Recent Key Publications
- 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 and Randi AM. Dynamic regulation of canonical TGFβ signaling by endothelial transcription factor ERG protects from liver fibrogenesis Nat Commun. 2017 in press
- K E Paschalaki, A Zampetaki, J R Baker, M A Birrell, R D. Starke, M G Belvisi, L Donnelly, M Mayr, A M Randi*, P J Barnes1* (*shared senior). Downregulation of microRNA-126 augments DNA damage response in cigarette smokers and COPD patients. AJRCMM, in press
- Shah AV, Birdsey GM, Peghaire C, Pitulescu ME, Dufton NP, Yang Y, Weinberg I, Osuna Almagro L, Payne L, Mason JC, Gerhardt H, Adams RH, Randi AM. The endothelial transcription factor ERG mediates Angiopoietin-1-dependent control of Notch signalling and vascular stability. Nat Commun. 2017 Jul 11;8:16002.
- Randi AM. and Laffan MA. von Willebrand factor and angiogenesis: basic and applied issues. J Thromb Haemost. 2017 Jan;15(1):13-20
- Shah AV, Birdsey GM and Randi AM Regulation of endothelial homeostasis, vascular development and angiogenesis by the transcription factor ERG (Vascular Pharmacology, 2016 Nov;86:3-13)
- Birdsey GM, Shah A V, Reynolds LE, Dufton N, Osuna Almagro L, Yang Y, Aspalter IM, Khan ST, Mason JC, Dejana E, Göttgens B, Hodivala-Dilke K, Gerhardt H, Adams RH, and Randi AM. The endothelial transcription factor ERG promotes vascular stability and growth through Wnt/b-catenin signalling. Developmental cell 2015; 32(1):82-96
- Paschalaki, K; Starke, R; Mercado, N; Gorgoulis, V; Barnes, P*; Randi, AM*. Dysfunction of endothelial progenitor cells from smokers and COPD patients due to increased DNA damage and senescence Stem Cell, 31(12):2813-26 (*shared senior authorship)
- Starke R, Paschalaki K, Dyer C, Harrison-Lavoie K, Cutler J, McKinnon T, Millar C, Cutler D, Laffan M, Randi AM. Cellular and molecular basis of Von Willebrand Disease: studies on blood outgrowth endothelial cells. Blood;121:2773-84; 2013
- NH Dryden, A Sperone, RL Hannah, GM Birdsey, S Taufiq Khan, JA Layhadi, JC Mason, DO Haskard, B Göttgens, AM. Randi The transcription factor Erg maintains endothelial quiescence by repressing NF-κB- dependent activity transcription through a novel ETS:NF-κB motif Journal Biological Chemistry, 287(15):12331-42;2012
- GM. Birdsey, NH. Dryden, AV. Shah, R. Hannah, M Hall, DO. Haskard, M Parsons, JC. Mason, M Zvelebil, B Gottgens, AJ Ridley, AM. Randi The transcription factor Erg regulates expression of histone deacetylase 6 and multiple pathways involved in endothelial cell migration and angiogenesis Blood. 119(3):894-903;2012
- Starke R, Paschalaki K, Ferraro F, Hughes A, Payne L, McKinnon T, Sutton R, Cutler D, Laffan M, Randi AM. Endothelial von Willebrand Factor regulates angiogenesis Blood,117:1071-80;2011
- Sperone A, Dryden NH, Birdsey GM, Madden L, Johns MJ, Evans PC, Mason JC, Boyle JJ, Haskard DO, Paleolog E, Randi AM The transcription factor Erg inhibits ICAM-1 expression and vascular inflammation. Atherosclerosis, Thrombosis and Vascular Biology, 31:142-50;2011
- Randi AM, Sperone, A, Dryden NH, Birdsey GM Regulation of angiogenesis by ETS transcription factors. Biochemical Society Transactions. 37:1248-53;2009
- GM Birdsey, NH Dryden, V Amsellem, F Gebhardt, K Sahnan, DO Haskard, E Dejana, JC Mason, Randi AM. The transcription factor Erg regulates angiogenesis and endothelial apoptosis through VE-cadherin. Blood. 111(7):3498-506; 2008
PI: Anna M. Randi (MD PhD)
Postdoctoral fellows: Dr. Neil Dufton
Clinical fellows: Dr. Koralia Paschalaki
BHF Research fellow: Dr. Claudio Ramondi
PhD students: Ms Viktoria Kalna
Ms Josefin Jansson Edqvist
Ms Oisin King
Research Assistant: Ms Linda Inuabasi
- Ralf Adams (Munster University, Germany)
- Shahin Rafii (Cornell, USA)
- Mike Simons (Yale, USA)
- David Adams (Birmingham, UK)
- Mike Laffan (London, UK)
- Justin Mason (London, UK)
- 9th International BIC meeting, Rome, Italy – September 2017
- Angiogenesis Gordon Research Conference (GRC) – Salve Regina, RI, USA – August 2017
- International Society on Thrombosis and Haemostasis (ISTH) Meeting, Berlin July 2017
- 2nd Joint European Microcirculation Society - European Vascular Biology (EVBO) meeting, Geneva - May 2017
- Society of Thrombosis and Hemostasis Research (GTH) Basel, February 2017 (Plenary Lecture)