{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:09:19Z","timestamp":1790795359990,"version":"4.1.0"},"reference-count":42,"publisher":"The Company of Biologists","issue":"4","license":[{"start":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T00:00:00Z","timestamp":1680134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"crossref","award":["PG\/20\/10017"],"award-info":[{"award-number":["PG\/20\/10017"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"crossref","award":["PG\/18\/57\/33941"],"award-info":[{"award-number":["PG\/18\/57\/33941"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"crossref","award":["IG\/15\/1\/31328"],"award-info":[{"award-number":["IG\/15\/1\/31328"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Research Council"},{"DOI":"10.13039\/501100000858","name":"University of Sheffield","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100000858","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Hereditary haemorrhagic telangiectasia (HHT) causes arteriovenous malformations (AVMs) in multiple organs to cause bleeding, neurological and other complications. HHT is caused by mutations in the BMP co-receptor endoglin. We characterised a range of vascular phenotypes in embryonic and adult endoglin mutant zebrafish and the effect of inhibiting different pathways downstream of Vegf signalling. Adult endoglin mutant zebrafish developed skin AVMs, retinal vascular abnormalities and cardiac enlargement. Embryonic endoglin mutants developed an enlarged basilar artery (similar to the previously described enlarged aorta and cardinal vein) and larger numbers of endothelial membrane cysts (kugeln) on cerebral vessels. Vegf inhibition prevented these embryonic phenotypes, leading us to investigate specific Vegf signalling pathways. Inhibiting mTOR or MEK pathways prevented abnormal trunk and cerebral vasculature phenotypes, whereas inhibiting Nos or Mapk pathways had no effect. Combined subtherapeutic mTOR and MEK inhibition prevented vascular abnormalities, confirming synergy between these pathways in HHT. These results indicate that the HHT-like phenotype in zebrafish endoglin mutants can be mitigated through modulation of Vegf signalling. Combined low-dose MEK and mTOR pathway inhibition could represent a novel therapeutic strategy in HHT.<\/jats:p>","DOI":"10.1242\/dmm.049567","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T06:25:35Z","timestamp":1677738335000},"source":"Crossref","is-referenced-by-count":11,"title":["Therapeutic targeting of vascular malformation in a zebrafish model of hereditary haemorrhagic telangiectasia"],"prefix":"10.1242","volume":"16","author":[{"given":"Ryan O.","family":"Snodgrass","sequence":"first","affiliation":[{"name":"Medical School, University of Sheffield 1 Department of Infection, Immunity and Cardiovascular Disease , , Sheffield S10 2RX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3796-1983","authenticated-orcid":false,"given":"Karan","family":"Govindpani","sequence":"additional","affiliation":[{"name":"Medical School, University of Sheffield 1 Department of Infection, Immunity and Cardiovascular Disease , , Sheffield S10 2RX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Plant","sequence":"additional","affiliation":[{"name":"Medical School, University of Sheffield 1 Department of Infection, Immunity and Cardiovascular Disease , , Sheffield S10 2RX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2536-6140","authenticated-orcid":false,"given":"Elisabeth C.","family":"Kugler","sequence":"additional","affiliation":[{"name":"Medical School, University of Sheffield 1 Department of Infection, Immunity and Cardiovascular Disease , , Sheffield S10 2RX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changmin","family":"Doh","sequence":"additional","affiliation":[{"name":"Medical School, University of Sheffield 1 Department of Infection, Immunity and Cardiovascular Disease , , Sheffield S10 2RX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Dawson","sequence":"additional","affiliation":[{"name":"Medical School, University of Sheffield 1 Department of Infection, Immunity and Cardiovascular Disease , , Sheffield S10 2RX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis E.","family":"McCormack","sequence":"additional","affiliation":[{"name":"Medical School, University of Sheffield 1 Department of Infection, Immunity and Cardiovascular Disease , , Sheffield S10 2RX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen M.","family":"Arthur","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Centre for Life, Newcastle University 2 , Newcastle NE1 3BZ , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7458-5481","authenticated-orcid":false,"given":"Timothy J. A.","family":"Chico","sequence":"additional","affiliation":[{"name":"Medical School, University of Sheffield 1 Department of Infection, Immunity and Cardiovascular Disease , , Sheffield S10 2RX , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2023,3,30]]},"reference":[{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1161\/ATVBAHA.118.310760","article-title":"ALK1 loss results in vascular hyperplasia in mice and humans through PI3K activation","volume":"38","author":"Alsina-Sanch\u00eds","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2023033014513490500_","first-page":"546","article-title":"Continual low-level MEK inhibition ameliorates cardio-facio-cutaneous phenotypes in zebrafish","volume":"5","author":"Anastasaki","year":"2012","journal-title":"Dis. Model. Mech."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"973964","DOI":"10.3389\/fmed.2022.973964","article-title":"An update on preclinical models of hereditary haemorrhagic telangiectasia: Insights into disease mechanisms","volume":"9","author":"Arthur","year":"2022","journal-title":"Front. Med."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1006\/dbio.1999.9534","article-title":"Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development","volume":"217","author":"Arthur","year":"2000","journal-title":"Dev. Biol."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1083\/jcb.201603106","article-title":"Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia","volume":"214","author":"Baeyens","year":"2016","journal-title":"J. Cell Biol."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1007\/s10456-019-09701-0","article-title":"BMP10-mediated ALK1 signaling is continuously required for vascular development and maintenance","volume":"23","author":"Capasso","year":"2020","journal-title":"Angiogenesis"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"30034","DOI":"10.1074\/jbc.M111.260133","article-title":"Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth","volume":"286","author":"Castonguay","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1101\/gad.1629408","article-title":"Foxn4 directly regulates tbx2b expression and atrioventricular canal formation","volume":"22","author":"Chi","year":"2008","journal-title":"Genes Dev."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.1242\/dev.060467","article-title":"Interaction between alk1 and blood flow in the development of arteriovenous malformations","volume":"138","author":"Corti","year":"2011","journal-title":"Development"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"948","DOI":"10.1001\/jama.2012.250","article-title":"Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output","volume":"307","author":"Dupuis-Girod","year":"2012","journal-title":"JAMA"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1056\/NEJM199510053331407","article-title":"Hereditary hemorrhagic telangiectasia","volume":"333","author":"Guttmacher","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1007\/s10456-014-9436-3","article-title":"VEGF neutralization can prevent and normalize arteriovenous malformations in an animal model for hereditary hemorrhagic telangiectasia 2","volume":"17","author":"Han","year":"2014","journal-title":"Angiogenesis"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1161\/CIRCRESAHA.119.316267","article-title":"Overexpression of activin receptor-like kinase 1 in endothelial cells suppresses development of arteriovenous malformations in mouse models of hereditary hemorrhagic telangiectasia","volume":"127","author":"Hwan Kim","year":"2020","journal-title":"Circ. Res."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1161\/CIRCRESAHA.120.317722","article-title":"Oncogenes in Brain Arteriovenous Malformations","volume":"127","author":"Jakobsson","year":"2020","journal-title":"Circ. Res."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/ncb3534","article-title":"Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling","volume":"19","author":"Jin","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1038\/ng0696-189","article-title":"Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2","volume":"13","author":"Johnson","year":"1996","journal-title":"Nat. Genet."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"e47047","DOI":"10.15252\/embr.201847047","article-title":"Cerebrovascular endothelial cells form transient Notch-dependent cystic structures in zebrafish","volume":"20","author":"Kugler","year":"2019","journal-title":"EMBO Rep."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"dev199720","DOI":"10.1242\/dev.199720","article-title":"Zebrafish Vascular Quantification: a tool for quantification of three-dimensional zebrafish cerebrovascular architecture by automated image analysis","volume":"149","author":"Kugler","year":"2022","journal-title":"Development"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"17800","DOI":"10.1073\/pnas.1816661116","article-title":"Role of soluble endoglin in BMP9 signaling","volume":"116","author":"Lawera","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"4018","DOI":"10.1038\/sj.emboj.7600386","article-title":"Endoglin promotes endothelial cell proliferation and TGF-beta\/ALK1 signal transduction","volume":"23","author":"Lebrin","year":"2004","journal-title":"EMBO J."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1126\/science.284.5419.1534","article-title":"Defective angiogenesis in mice lacking endoglin","volume":"284","author":"Li","year":"1999","journal-title":"Science"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1161\/CIRCRESAHA.109.211037","article-title":"Pathogenesis of arteriovenous malformations in the absence of endoglin","volume":"106","author":"Mahmoud","year":"2010","journal-title":"Circ. Res."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/ng1294-345","article-title":"Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1","volume":"8","author":"McAllister","year":"1994","journal-title":"Nat. Genet."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1111\/gtc.12438","article-title":"ERK activation in endothelial cells is a novel marker during neovasculogenesis","volume":"21","author":"Nagasawa-Masuda","year":"2016","journal-title":"Genes Cells"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1056\/NEJMoa1709449","article-title":"Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain","volume":"378","author":"Nikolaev","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"13650","DOI":"10.1038\/ncomms13650","article-title":"PI3 kinase inhibition improves vascular malformations in mouse models of hereditary haemorrhagic telangiectasia","volume":"7","author":"Ola","year":"2016","journal-title":"Nat. Commun."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1161\/CIRCULATIONAHA.120.053047","article-title":"Defective flow-migration coupling causes arteriovenous malformations in hereditary hemorrhagic telangiectasia","volume":"144","author":"Park","year":"2021","journal-title":"Circulation"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"4539","DOI":"10.1007\/s00018-017-2636-4","article-title":"ALK1 signaling in development and disease: new paradigms","volume":"74","author":"Roman","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"3009","DOI":"10.1242\/dev.129.12.3009","article-title":"Disruption of acvrl1 increases endothelial cell number in zebrafish cranial vessels","volume":"129","author":"Roman","year":"2002","journal-title":"Development"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1172\/JCI127425","article-title":"Correcting Smad1\/5\/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models","volume":"130","author":"Ruiz","year":"2020","journal-title":"J. Clin. Invest."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1242\/jcs.002949","article-title":"BMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesis","volume":"120","author":"Scharpfenecker","year":"2007","journal-title":"J. Cell Sci."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1016\/j.blre.2010.07.001","article-title":"Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment","volume":"24","author":"Shovlin","year":"2010","journal-title":"Blood Rev."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"174","DOI":"10.3390\/genes12020174","article-title":"Hereditary haemorrhagic telangiectasia, an inherited vascular disorder in need of improved evidence-based pharmaceutical interventions","volume":"12","author":"Snodgrass","year":"2021","journal-title":"Genes"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1038\/ncb3528","article-title":"Endoglin controls blood vessel diameter through endothelial cell shape changes in response to haemodynamic cues","volume":"19","author":"Sugden","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"2934","DOI":"10.1096\/fj.201700867RR","article-title":"Endoglin interacts with VEGFR2 to promote angiogenesis","volume":"32","author":"Tian","year":"2018","journal-title":"FASEB J."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"684","DOI":"10.1161\/01.RES.0000159936.38601.22","article-title":"A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia","volume":"96","author":"Toporsian","year":"2005","journal-title":"Circ. Res."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"e006278","DOI":"10.1161\/JAHA.117.006278","article-title":"Cardiovascular adverse events in patients with cancer treated with bevacizumab: a meta-analysis of more than 20\u2009000 patients","volume":"6","author":"Totzeck","year":"2017","journal-title":"J. Am. Heart Assoc"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"e98646","DOI":"10.1371\/journal.pone.0098646","article-title":"Endothelial depletion of Acvrl1 in mice leads to arteriovenous malformations associated with reduced endoglin expression","volume":"9","author":"Tual-Chalot","year":"2014","journal-title":"PLoS ONE"},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"25","DOI":"10.3389\/fgene.2015.00025","article-title":"Mouse models of hereditary hemorrhagic telangiectasia: recent advances and future challenges","volume":"6","author":"Tual-Chalot","year":"2015","journal-title":"Front. Genet."},{"key":"2023033014513490500_","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1161\/CIRCRESAHA.119.315974","article-title":"Loss of endothelial endoglin promotes high-output heart failure through peripheral arteriovenous shunting driven by VEGF signaling","volume":"126","author":"Tual-Chalot","year":"2020","journal-title":"Circ. Res."},{"key":"2023033014513490500_","first-page":"56674","article-title":"Studying diabetes through the eyes of a fish: microdissection, visualization, and analysis of the adult tg(fli:EGFP) zebrafish retinal vasculature","volume":"26","author":"Wiggenhauser","year":"2017","journal-title":"J. Vis. Exp."}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.049567\/2570808\/dmm049567.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.049567\/2762947\/dmm049567.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.049567\/2762947\/dmm049567.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,30]],"date-time":"2023-03-30T11:04:11Z","timestamp":1680174251000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/16\/4\/dmm049567\/304889\/Therapeutic-targeting-of-vascular-malformation-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,30]]},"references-count":42,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.049567","relation":{},"ISSN":["1754-8403","1754-8411"],"issn-type":[{"value":"1754-8403","type":"print"},{"value":"1754-8411","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,30]]},"article-number":"dmm049567"}}