Professor Helen Arthur
Professor of Cardiovascular Biology
- Email: email@example.com
- Telephone: +44 (0) 191 241 8648
- Fax: +44 (0) 191 241 8666
- Address: Institute of Genetic Medicine
International Centre for Life
Newcastle upon Tyne
TGFβ Receptors in Cardiovascular Development and Disease
The formation of new blood vessels, angiogenesis, is an essential developmental process that is also a target for treating many major diseases. For example, coronary heart disease causes the obstruction of blood vessels supplying heart tissue, leading to cardiac cell death. Here, increasing angiogenesis can re-establish the blood supply to minimise heart damage.
Angiogenesis is regulated by a number of molecular signalling pathways and our work revolves around receptors in the TGFβ family signalling pathway. The importance of the TGFβ family of ligands in regulating angiogenesis and cardiovascular development was established in human genetic studies where inherited mutations in several TGFβ receptors leads to congenital cardiovascular abnormalities. For example, mutations in the receptors, endoglin or activin like kinase-1 (ACVRL1), are associated with the inherited bleeding disorder, Hereditary Haemorrhagic Telangiectasia (HHT).
Using a combination of mouse genetics and cell culture systems, we have shown that endoglin is essential for cardiovascular development, is dynamically regulated during angiogenesis, and that depletion of endoglin in the context of an angiogenic trigger (such as developmental angiogenesis or inflammation) leads to arteriovenous malformations, a major clinical feature of HHT disease. We have shown that adult heart cells, cultured from biopsies and known as cardiospheres, contribute to the repair of heart function following myocardial infarction (a heart attack). We have shown that endoglin expressed by cardiosphere derived cells is essential for promoting angiogenesis in the ischaemic heart.
More recently our work is addressing the problems caused by ischaemia reperfusion (I/R) injury in the heart. This injury occurs in acute heart attack patients who are successfully treated by an interventional cardiologist to re-open a blocked coronary artery. Much of the patient’s ischaemic myocardium can be saved by this rapid clinical intervention. However, the I/R injury that follows is due to inflammatory cells that invade the injured part of the heart and contribute to further damage. Suppressing this I/R response will improve outcomes for heart patients. We have shown that TGFbeta therapy is effective in reducing this injury and are currently investigating mechanisms that underlie this protective response and whether this therapy can be used in heart attack patients. In addition, in collaborative studies, we are investigating whether fractalkine, a protein that is dynamically regulated in cardiac I/R injury in patients, can be used as a target for therapy.
Our goals in both HHT and heart attack patients is to use preclinical models to better understand disease mechanisms in order to inform the development of improved therapies for patients.
Research TeamLilia Dragonova BSc BHF PhD student
Darroch Hall BSc PhD
Sarah Marsh BSc MRC DTP PhD student
Rachel Redgrave BSc PhD
BHF Research Associate
Esha Singh MSc
BHF Research Assistant
Simon Tual-Chalot PhD
BHF Research Associate
- Jin Y, Muhl L, Burmakin M, Wang Y, Duchez A-C, Betsholtz C, Arthur HM, Jakobsson L. Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling. Nature Cell Biology 2017, 19, 639-652.
- Dingenouts CKE, Bakker W, Lodder K, Wiesmeijer KC, Moerkamp AT, Maring JA, Arthur HM, Smits AM, Goumans MJ. Inhibiting DPP4 in a mouse model of HHT1 results in a shift towards regenerative macrophages and reduces fibrosis after myocardial infarction. PLoS One 2017, 12, e0189805.
- Marsh SA, Arthur HM, Spyridopoulos I. The secret life of nonclassical monocytes. Cytometry Part A 2017, 91(11), 1055-1058.
- Redgrave RE, Tual-Chalot S, Davison BJ, Singh E, Hall D, Amirrasouli MM, Gilchrist D, Medvinsky A, Arthur HM. Cardiosphere-Derived Cells Require Endoglin for Paracrine-Mediated Angiogenesis. Stem Cell Reports 2017, 8(5), 1287-1298.
- Spyridopoulos I, Arthur HM. Microvessels of the Heart: formation, regeneration and dysfunction. Microcirculation 2016, Epub ahead of print.
- Redgrave RE, Tual-Chalot S, Davison BJ, Greally E, Santibanez-Koref M, Schneider JE, Blamire AM, Arthur HM. Using MRI to predict future adverse cardiac remodelling in a male mouse model of myocardial infarction. IJC Heart & Vasculature 2016, 11, 29-34.
- Young K, Krebs LT, Tweedie E, Conley B, Mancini M, Arthur HM, Liaw L, Gridley T, Vary CPH. Endoglin is required in Pax3-derived cells for embryonic blood vessel formation. Developmental Biology 2016, 409(1), 95-105.
- Gkatzis K, Thalgott J, Dos-Santos-Luis D, Martin S, Lamandé N, Carette MF, Disch F, Snijder RJ, Westermann CJ, Mager JJ, Oh SP, Miquero lL, Arthur HM, Mummery CL, Lebrin F. Interaction Between ALK1 Signaling and Connexin40 in the Development of Arteriovenous Malformations. Arteriosclerosis, Thrombosis, and Vascular Biology 2016, 36(4), 707-717.
- Ojeda-Fernandez L, Recio-Poveda L, Aristorena M, Lastres P, Blanco FJ, Sanz-Rodríguez F, Gallardo-Vara E, de-las-Casas-Engel M, Corbí Á, Arthur HM, Bernabeu C, Botella LM. Mice Lacking Endoglin in Macrophages Show an Impaired Immune Response. PLoS Genetics 2016, 12(3), e1005935.
- Clarkin CE, Mahmoud M, Liu B, Sobamowo EO, King A, Arthur H, Jones PM, Wheeler-Jones CP. Modulation of endoglin expression in islets of langerhans by VEGF reveals a novel regulator of islet endothelial cell function. BMC Research Notes 2016, 9, 362.
- Zhang R, Han Z, Degos V, Shen F, Choi E-J, Kang S, Wong M, Zhan L, Arthur HM, Oh SP, Faughnan ME, Su H. Persistent infiltration and pro-inflammatory differentiation of monocytes causing unresolved inflammation in brain arteriovenous malformation. Angiogenesis 2016, (ePub ahead of Print), 1-11.
- Tual-Chalot S, Oh SP, Arthur HM. Mouse models of hereditary hemorrhagic telangiectasia: recent advances and future challenges. Frontiers in Genetics 2015, 6, 25.
- Garrido-Martin EM, Nguyen HL, Cunningham TA, Choe SW, Jiang ZH, Arthur HM, Lee YJ, Oh SP. Common and Distinctive Pathogenetic Features of Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia 1 and Hereditary Hemorrhagic Telangiectasia 2 Animal Models-Brief Report. Arteriosclerosis, Thrombosis and Vascular Biology 2014, 34(10), 2232-2236.
- Liu Z, Lebrin F, Maring JA, van den Driesche S, van der Brink S, van Dinther M, Thorikay M, Martin S, Kobayashi K, Hawinkels LJAC, van Meeteren LA, Pardali E, Korving J, Letarte M, Arthur HM, Theuer C, Goumans MJ, Mummery C, ten Dijke P. ENDOGLIN Is Dispensable for Vasculogenesis, but Required for Vascular Endothelial Growth Factor-Induced Angiogenesis. PLoS One 2014, 9(1), e86273.
- Tual-Chalot S, Mahmoud M, Allinson KR, Redgrave RE, Zhai ZH, Oh SP, Fruttiger M, Arthur HM. Endothelial Depletion of Acvrl1 in Mice Leads to Arteriovenous Malformations Associated with Reduced Endoglin Expression. PLoS One 2014, 9(6), e98646.
- Choi EJ, Chen WQ, Jun K, Arthur HM, Young WL, Su H. Novel Brain Arteriovenous Malformation Mouse Models for Type 1 Hereditary Hemorrhagic Telangiectasia. PLOS One 2014, 9(2), e88511.
- Anderberg C, Cunha S, Zhai Z, Cortez E, Pardali E, Johnson J, Franco M, Paez-Ribes M, Cordiner R, Fuxe J, Johansson BR, Goumans MJ, Casanovas O, ten Dijke P, Arthur HM, Pietras K. Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination. Journal of Experimental Medicine 2013, 210(3), 563-579.
- Wang X, Abraham S, McKenzie JAG, Jeffs N, Swire M, Tripathi VB, Luhmann UFO, Lange CAK, Zhai Z, Arthur HM, Bainbridge J, Moss SE, Greenwood J. LRG1 promotes angiogenesis by modulating endothelial TGFß signalling. Nature 2013, 499, 306-311.
- Ehrmann I, Dalgliesh C, Liu Y, Danilenko M, Crosier M, Overman L, Arthur HM, Lindsay S, Clowry GJ, Venables JP, Fort P, Elliott DJ. The Tissue-Specific RNA Binding Protein T-STAR Controls Regional Splicing Patterns of Neurexin Pre-mRNAs in the Brain. PLoS Genetics 2013, 9(4), e1003474.
- Tual-Chalot S, Allinson KR, Fruttiger M, Arthur HM. Whole Mount Immunofluorescent Staining of the Neonatal Mouse Retina to Investigate Angiogenesis In vivo. Journal of Visualized Experiments 2013, 77, 1-5.
- Watkins SJ, Borthwick GM, Oakenfull R, Robson A, Arthur HM. Angiotensin II-induced cardiomyocyte hypertrophy in vitro is TAK1-dependent and Smad2/3-independent. Hypertension Research 2012, 35(4), 393-398.
- Allinson KR, Lee HS, Fruttiger M, McCarty J, Arthur HM. Endothelial Expression of TGF beta Type II Receptor Is Required to Maintain Vascular Integrity during Postnatal Development of the Central Nervous System. PLoS One 2012, 7(6), e39336.
- Choi EJ, Walker EJ, Shen FX, Oh SP, Arthur HM, Young WL, Su H. Minimal Homozygous Endothelial Deletion of Eng with VEGF Stimulation Is Sufficient to Cause Cerebrovascular Dysplasia in the Adult Mouse. Cerebrovascular Diseases 2012, 33(6), 540-547.
- Tan HL, Glen E, Topf A, Hall D, O'Sulliyan JJ, Sneddon L, Wren C, Avery P, Lewis RJ, ten Dijke P, Arthur HM, Goodship JA, Keavney BD. Nonsynonymous variants in the SMAD6 gene predispose to congenital cardiovascular malformation. Human Mutation 2012, 33(4), 720-727.
- Mahmoud M, Upton P, Arthur HM. Angiogenesis Regulation by TGFbeta signalling: clues from an inherited vascular disease. Biochemical Society Transactions 2011, 39(6), 1659-1666.
- Arthur HM, Bamforth SD. TGF beta Signaling and Congenital Heart Disease: Insights from Mouse Studies. Birth Defects Research Part A: Clinical and Molecular Teratology 2011, 91(6), 423-434.
- Watkins SJ, Borthwick GM, Arthur HM. The H9C2 cell line and primary neonatal cardiomyocyte cells show similar hypertrophic responses in vitro. In Vitro Cellular & Developmental Biology: Animal 2011, 47(2), 125-131.
- Mahmoud M, Allinson KR, Zhai ZH, Oakenfull R, Ghandi P, Adams RH, Fruttiger M, Arthur HM. Pathogenesis of Arteriovenous Malformations in the Absence of Endoglin. Circulation Research 2010, 106(8), 1425-1433.
- Lebrin F, Srun S, Raymond K, Martin S, van den Brink S, Freitas C, Breant C, Mathivet T, Larrivee B, Thomas JL, Arthur HM, Westermann CJJ, Disch F, Mager JJ, Snijder RJ, Eichmann A, Mummery CL. Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nature Medicine 2010, 16(4), 420-428.
- Robson A, Allinson KR, Anderson RH, Henderson DJ, Arthur HM. The TGF beta Type II Receptor Plays a Critical Role in the Endothelial Cells During Cardiac Development. Developmental Dynamics 2010, 239(9), 2435-2442.
- Mahmoud M, Borthwick GM, Hislop A, Arthur HM. Endoglin and activin receptor-like-kinase 1 are co-expressed in the distal vessels of the lung: implications for two familial vascular dysplasias, HHT and PAH. Laboratory Investigation 2009, 89(1), 15-25.
- Thomas HE, Avery PJ, Ahmed JM, Edwards R, Purcell I, Zaman AG, Arthur HM, Keavney BD. Local vessel injury following percutaneous coronary intervention does not promote early mobilisation of endothelial progenitor cells in the absence of myocardial necrosis. Heart 2009, 95(7), 555-558.
- Thomas HE, Redgrave R, Cunnington MS, Avery P, Keavney BD, Arthur HM. Circulating endothelial progenitor cells exhibit diurnal variation. Arteriosclerosis, Thrombosis, and Vascular Biology 2008, 28(3), e21-e22.
- Ten Dijke P, Arthur HM. Extracellular control of TGFβ signalling in vascular development and disease. Nature Reviews Molecular Cell Biology 2007, 8(11), 857-869.
- Allinson KR, Carvalho RLC, Van Den Brink S, Mummery CL, Arthur HM. Generation of a floxed allele of the mouse endoglin gene. Genesis: The Journal of Genetics and Development 2007, 45(6), 391-395.
- Watkins SJ, Jonker L, Arthur HM. A direct interaction between TGFβ activated kinase 1 and the TGFβ type II receptor: Implications for TGFβ signalling and cardiac hypertrophy. Cardiovascular Research 2006, 69(2), 432-439.
- Van Laake LW, Van Den Driesche S, Post S, Feijen A, Jansen MA, Driessens MH, Mager JJ, Snijder RJ, Westermann CJJ, Doevendans PA, Van Echteld CJA, Ten Dijke P, Arthur HM, Goumans M-J, Lebrin F, Mummery CL. Endoglin has a crucial role in blood cell-mediated vascular repair. Circulation 2006, 114(21), 2288-2297.
- Borthwick GM, Johnson AS, Partington M, Burn J, Wilson R, Arthur HM. Therapeutic levels of aspirin and salicylate directly inhibit a model of angiogenesis through a Cox-independent mechanism. The FASEB Journal 2006, 20(12), 2009-2016.
- Carvalho RLC, Jonker L, Goumans M-J, Larsson J, Bouwman P, Karlsson S, ten Dijke P, Arthur HM, Mummery CL. Defective paracrine signalling by TGFβ in yolk sac vasculature of endoglin mutant mice: A paradigm for hereditary haemorrhagic telangiectasia. Development 2004, 131(24), 6237-6247.
- Lebrin F, Goumans M-J, Jonker L, Carvalho RLC, Valdimarsdottir G, Thorikay M, Mummery C, Arthur HM, Ten Dijke P. Endoglin promotes endothelial cell proliferation and TGF-β/ALK1 signal transduction. EMBO Journal 2004, 23(20), 4018-4028.
- Xu B, Wu YQ, Huey M, Arthur HM, Marchuk DA, Hashimoto T, Young WL, Yang G-Y. Vascular Endothelial Growth Factor Induces Abnormal Microvasculature in the Endoglin Heterozygous Mouse Brain. Journal of Cerebral Blood Flow and Metabolism 2004, 24(2), 237-244.
- Torsney E, Charlton R, Diamond AG, Burn J, Soames JV, Arthur HM. Mouse model for hereditary hemorrhagic telangiectasia has a generalized vascular abnormality. Circulation 2003, 107(12), 1653-1657.
- Kettle C, Johnstone J, Jowett T, Arthur H, Arthur W. The pattern of segment formation, as revealed by engrailed expression, in a centipede with a variable number of segments. Evolution and Development 2003, 5(2), 198-207.
- Jonker L, Arthur HM. Endoglin expression in early development is associated with vasculogenesis and angiogenesis. Mechanisms of Development 2002, 110(1-2), 193-196.
- Torsney E, Charlton R, Parums D, Collis M, Arthur HM. Inducible expression of human endoglin during inflammation and wound healing in vivo. Inflammation Research 2002, 51(9), 464-470.
- Arthur HM, Ure J, Smith AJH, Renforth G, Wilson DI, Torsney E, Charlton R, Parums DV, Jowett T, Marchuk DA, Burn J, Diamond AG. Endoglin, an ancillary TGFβ receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Developmental Biology 2000, 217(1), 42-53.
- Andrejecsk JW, Hosman AE, Botella LM, Shovlin CL, Arthur HM, Dupuis-Girod S, Buscarini E, Hughes CCW, Lebrin F, Mummery CL, Post MC, Mager JJ. Executive summary of the 12th HHT international scientific conference. Angiogenesis 2018, 21(1), 169-181.