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. Endothelial cells also contribute to tissue homeostasis, making this area critical for a wide number of diseases and for regenerative medicine.
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. We have found a new Master regulator of endothelial homeostasis, the ETS related gene ERG, which is the most highly expressed ETS transcription factor in healthy endothelial cells. ERG is essential for vascular development and angiogenesis (Birdsey, Dev Cell 2015; Shah, Nature Comms 2017), and to maintain endothelial homeostasis, by driving and repressing gene expression. ERG protects cells from endothelial-to-mesenchymal (EndMT) transition, a process implicated in diseases including atherosclerosis and liver fibrosis (Dufton, Nature Comms 2017). ERG also contributes to maintain the anti-thrombotic phenotype of endothelial cells, by driving the expression of Thrombomodulin (Peghaire, Nature Coms 2019). In line with its protective role, ERG endothelial expression is lost in tissue samples from patients with atherosclerosis, chronic liver fibrosis and other inflammatory diseases. Recently, in collaboration with the Rafii lab at Weill-Cornell University (NY, USA), we have shown that ERG, with its homolog Fli1, is essential to maintain vascular integrity; the combined loss of these ETS factors results in dramatic vascular collapse, systemic inflammation and death (Gomez-Salinero, Nature CV Research 2022). Current studies aim to identify what causes ERG loss in disease, and how to restore its levels in endothelial cells.
The other major project in the group focuses on the role of Von Willebrand Factor (VWF), a key haemostatic protein, in angiogenesis and vascular integrity. decrease or dysfunction of VWF causes Von Willebrand Disease (VWD), the most common genetic bleeding disorder. 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 (Starke, Blood 2011) opened the way to a novel concept for the management of these patients. We identified Angiopoietin-2 and VEGFR2 and two key pathway contributing to vascular dysfunction in VWD. We have also demonstrated that VWF interacts with multiple growth factors (Ishihara, Blood 2019), suggesting yet more undiscovered functions for this amazing protein. We are using Endothelial Colony Forming Cells (ECFC) isolated from circulating blood and developing organotypic models to validate some of the pathways controlled by VWF, with the aim to provide novel therapeutic targets for the management of GI bleeding in VWD.
We are interested in translating our endothelial research in patients; for this reason, we have used ECFC to study patients with chronic obstructive pulmonary disease (COPD), who often present with cardiovascular (CV) complications and develop endothelial dysfunction due to cigarette smoke. Dr. Koralia Paschalaki in the group has shown that ECFC from these patients retain epigenetic dysfunction, which can be corrected by pharmacological treatment. Thus, ECFC 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
- Schafer CM, Martin-Almedina S, Kurylowicz K, Dufton N, Osuna-Almagro L, Wu ML, Johnson CF, Shah AV, Haskard DO, Buxton A, Willis E, Wheeler K, Turner S, Chlebicz M, Scott RP, Kovats S, Cleuren A, Birdsey GM, Randi AM* and Griffin CT* (*Shared Senior). Cytokine-Mediated Degradation of the Transcription Factor ERG Impacts the Pulmonary Vascular Response to Systemic Inflammatory Challenge. bioRxiv. 2023 Feb 11:2023.02.08.527788. doi: 10.1101/2023.02.08.527788. Preprint.
- JM Gomez-Salinero, T. Itkin1, S Houghton, C Badwe, Y Lin, V Kalna, N Dufton, CR Peghaire, M Yokoyama, M Wingo, T Liu, G Li, JZ Xiang, Y Sheng Hsu, D Redmond, R Schreiner, GM Birdsey, AM Randi* and S Rafii* (*Shared Senior). Cooperative ETS Transcription Factors Enforce Adult Endothelial Cell Fate and Cardiovascular Homeostasis. Nature Cardiovascular Research. 2022 Oct;1:882-899. doi: 10.1038/s44161-022-00128-3.
- Paschalaki K, Rossios C, Pericleous C, MacLeod, Rothery S, Donaldson GC, Wedzicha JA, Gorgoulis V, Randi AM*, Barnes PJ* Inhaled corticosteroids reduce senescence in endothelial progenitor cells from patients with COPD. Thorax Jun;77(6):616-620. doi: 10.1136/thoraxjnl-2020-216807
- McCracken IR, Saginc G, He L, Huseynov A, Daniels A, Fletcher S, Peghaire C, Kalna V, Andaloussi-Mäe M, Muhl L, Craig NM, Griffiths SJ, Haas JG, Tait-Burkard C, Lendahl U, Birdsey GM, Betsholtz C, Noseda M, Baker AH, Randi AM. Lack of Evidence of ACE2 Expression and Replicative Infection by SARSCoV-2 in Human Endothelial Cells. Circulation. 2021 Jan 6. doi: 10.1161/CIRCULATIONAHA.120.052824.
- C. Peghaire, NP. Dufton, M. Lang, II. Salles-Crawley, J. Ahnström, V. Kalna, C. Raimondi, C. Pericleous, L. Inuabasi, JC. Mason, GM. Birdsey, AM Randi. An endothelial homeostatic pathway preventing spontaneous microvascular thrombosis controlled by the transcription factor ERG. Nature Comm 2019; 10: 5014.
- Smadja DM, Melero-Martin JM, Eikenboom J, Bowman M, Sabatier F, Randi AM. 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. J Thromb Haemost. 2019 Jul;17(7):1190-1194. doi: 10.1111/jth.14462.
- Ishihara J, Ishihara A, Starke RD, Peghaire CR, Smith KE, McKinnon TA, Tabata Y, Sasaki K, White MJ, Fukunaga K, Laffan MA, Lutolf MP, Randi AM*, Hubbell JA* (*shared senior). The heparin binding domain of von Willebrand factor binds to growth factors and promotes angiogenesis in wound healing. Blood. 2019 Apr 11. pii: blood.2019000510. doi: 10.1182/blood.2019000510.
- Kalna V, Yang Y, Peghaire CR, Frudd K, Hannah R, Shah AV, Osuna Almagro L, Boyle JJ, Göttgens B, Ferrer J, Randi AM*, Birdsey GM* (*shared senior). The Transcription Factor ERG Regulates Super-Enhancers Associated With an Endothelial-Specific Gene Expression Program. Circulation Res. 2019 Apr 26;124(9):1337-1349. doi: 10.1161/CIRCRESAHA.118.313788.
- Randi AM, Smith KE, Castaman G. von Willebrand factor regulation of blood vessel formation. Blood. 2018 Jul 12;132(2):132-140. doi: 10.1182/blood-2018-01-769018. Epub 2018 Jun 4.
- Dufton NP, Peghaire CR, Osuna-Almagro L, Raimondi C, Kalna V, Chuahan A, Webb G, Yang Y, Birdsey GM, Lalor P, Mason JC, Adams DH, Randi AM. Dynamic regulation of canonical TGFβ signaling by endothelial transcription factor ERG protects from liver fibrogenesis. Nat Commun. 2017 ;8(1):895.
- 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. doi: 10.1038/ncomms16002.
- 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
PI: Anna M. Randi (MD PhD)
Postdoctoral fellows: Dr Ben Wiggins
Clinical fellows: Dr. Koralia Paschalaki
Dr. Deepa Arachchillage
PhD students: Ms Daisy Jones; Ms Elisa Giglio (visiting, University of Perugia, Italy)
Research Assistant: Ms Daisy Gresham
- Shahin Rafii (New York, USA)
- Ralf Adams (Munster, Germany)
- Marco Rasponi (Milano, Italy)
- Neil Dufton (London, UK)
- Serena Zacchigna (Triste, Italy)
- Mike Laffan (London, UK)
- Courtney Griffin (Oklahoma, USA)
- Benedetta Bussolati (Torino, Italy)
- Ines Cebola (London, UK)
- Luisa Iruela-Arispe (Chicago, USA)
- Justin Mason (London, UK)
Recent presentations by Prof. Randi include:
- Plenary Lecture at Vascular Discovery, American Heart Association September 2021
- Plenary Lecture, German Society of Transfusion Medicine and Immunohematology, Mannheim, Germany, September 2019
- State-of-the-art lecture at ISTH Meeting, Melbourne Australia July 2019
- Plenary Lecture at the Annual Meeting of the Society of Thrombosis and Hemostasis Research (GTH) Basel, Switzerland, Feb 2017.
- 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
- Plenary Lecture at Society of Thrombosis and Hemostasis Research (GTH) Basel, February 2017