{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:48:58Z","timestamp":1787021338579,"version":"build-2736575974"},"reference-count":47,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2017,1,15]],"date-time":"2017-01-15T00:00:00Z","timestamp":1484438400000},"content-version":"vor","delay-in-days":380,"URL":"http:\/\/www.biologists.com\/user-licence-1-1"}],"funder":[{"DOI":"10.13039\/100006955","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL079108"],"award-info":[{"award-number":["HL079108"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008408","name":"CureHHT","doi-asserted-by":"crossref","award":["12"],"award-info":[{"award-number":["12"]}],"id":[{"id":"10.13039\/100008408","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,1,1]]},"abstract":"<jats:p>Heterozygous loss of the arterial-specific TGF-\u03b2 type I receptor, activin receptor-like kinase 1 (ALK1), causes hereditary hemorrhagic telangiectasia (HHT). HHT is characterized by development of fragile, direct connections between arteries and veins, or arteriovenous malformations (AVMs). However, how decreased ALK1 signaling leads to AVMs is unknown. To understand the cellular missteps that cause AVMs, we assessed endothelial cell behavior in alk1-deficient zebrafish embryos, which develop cranial AVMs. Our data demonstrate that alk1 loss has no effect on arterial endothelial cell proliferation but alters arterial endothelial cell migration within lumenized vessels. In wild type embryos, alk1-positive cranial arterial endothelial cells generally migrate toward the heart, against the direction of blood flow, with some cells incorporating into endocardium. In alk1-deficient embryos, migration against flow is dampened and migration in the direction of flow is enhanced. Altered migration results in decreased endothelial cell number in arterial segments proximal to the heart and increased endothelial cell number in arterial segments distal to the heart. We speculate that the consequent increase in distal arterial caliber and hemodynamic load precipitates the flow-dependent development of downstream AVMs.<\/jats:p>","DOI":"10.1242\/dev.135392","type":"journal-article","created":{"date-parts":[[2016,6,11]],"date-time":"2016-06-11T00:31:44Z","timestamp":1465605104000},"source":"Crossref","is-referenced-by-count":84,"title":["Alk1 controls arterial endothelial cell migration in lumenized vessels"],"prefix":"10.1242","author":[{"given":"Elizabeth R.","family":"Rochon","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260, USA"},{"name":"Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prahlad G.","family":"Menon","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Duquesne University, Pittsburgh, PA 15110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1250-1705","authenticated-orcid":false,"given":"Beth L.","family":"Roman","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042608362834200_DEV135392C1","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1111\/1523-1747.ep12555569","article-title":"Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia","volume":"95","author":"Braverman","year":"1990","journal-title":"J. Invest. Dermatol."},{"key":"2021042608362834200_DEV135392C2","doi-asserted-by":"publisher","first-page":"e1001374","DOI":"10.1371\/journal.pbio.1001374","article-title":"Haemodynamics-driven developmental pruning of brain vasculature in zebrafish","volume":"10","author":"Chen","year":"2012","journal-title":"PLoS Biol."},{"key":"2021042608362834200_DEV135392C3","doi-asserted-by":"publisher","first-page":"11887","DOI":"10.1073\/pnas.1306074110","article-title":"Context-dependent signaling defines roles of BMP9 and BMP10 in embryonic and postnatal development","volume":"110","author":"Chen","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608362834200_DEV135392C4","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":"2021042608362834200_DEV135392C5","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1002\/jcp.21126","article-title":"Activin receptor-like kinase 1 inhibits human microvascular endothelial cell migration: potential roles for JNK and ERK","volume":"213","author":"David","year":"2007","journal-title":"J. Cell Physiol."},{"key":"2021042608362834200_DEV135392C6","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1161\/CIRCRESAHA.107.165530","article-title":"Bone morphogenetic protein-9 is a circulating vascular quiescence factor","volume":"102","author":"David","year":"2008","journal-title":"Circ. Res."},{"key":"2021042608362834200_DEV135392C7","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.devcel.2014.06.020","article-title":"Blood flow and Bmp signaling control endocardial chamber morphogenesis","volume":"30","author":"Dietrich","year":"2014","journal-title":"Dev. Cell"},{"key":"2021042608362834200_DEV135392C8","doi-asserted-by":"publisher","first-page":"e1002125","DOI":"10.1371\/journal.pbio.1002125","article-title":"Dynamic endothelial cell rearrangements drive developmental vessel regression","volume":"13","author":"Franco","year":"2015","journal-title":"PLoS Biol."},{"key":"2021042608362834200_DEV135392C9","doi-asserted-by":"publisher","first-page":"e07727","DOI":"10.7554\/elife.07727","article-title":"Non-canonical Wnt signalling modulates the endothelial shear stress flow sensor in vascular remodelling","volume":"5","author":"Franco","year":"2016","journal-title":"eLife"},{"key":"2021042608362834200_DEV135392C10","doi-asserted-by":"publisher","first-page":"852","DOI":"10.1016\/S0140-6736(04)15732-2","article-title":"A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4)","volume":"363","author":"Gallione","year":"2004","journal-title":"Lancet"},{"key":"2021042608362834200_DEV135392C11","doi-asserted-by":"publisher","first-page":"2232","DOI":"10.1161\/ATVBAHA.114.303984","article-title":"Common and distinctive pathogenetic features of arteriovenous malformations in hereditary hemorrhagic telangiectasia 1 and hereditary hemorrhagic telangiectasia 2 animal models--brief report","volume":"34","author":"Garrido-Martin","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021042608362834200_DEV135392C12","doi-asserted-by":"publisher","first-page":"960","DOI":"10.1038\/nprot.2006.96","article-title":"Cell tracking using a photoconvertible fluorescent protein","volume":"1","author":"Hatta","year":"2006","journal-title":"Nat. Protoc."},{"key":"2021042608362834200_DEV135392C13","doi-asserted-by":"publisher","first-page":"1942","DOI":"10.1016\/j.cub.2011.10.016","article-title":"Distinct cellular mechanisms of blood vessel fusion in the zebrafish embryo","volume":"21","author":"Herwig","year":"2011","journal-title":"Curr. Biol."},{"key":"2021042608362834200_DEV135392C14","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1161\/01.RES.0000089257.94002.96","article-title":"Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase","volume":"93","author":"Jin","year":"2003","journal-title":"Circ. Res."},{"key":"2021042608362834200_DEV135392C15","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":"2021042608362834200_DEV135392C16","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.devcel.2004.06.005","article-title":"A transposon-mediated gene trap approach identifies developmentally regulated genes in zebrafish","volume":"7","author":"Kawakami","year":"2004","journal-title":"Dev. Cell"},{"key":"2021042608362834200_DEV135392C17","first-page":"251","article-title":"The distribution of centrosomes in endothelial cells of the rat aorta and inferior vena cava","volume":"22","author":"Kiosses","year":"1997","journal-title":"Artery"},{"key":"2021042608362834200_DEV135392C18","doi-asserted-by":"publisher","first-page":"2891","DOI":"10.1161\/01.ATV.17.11.2891","article-title":"Evidence for the migration of rat aortic endothelial cells toward the heart","volume":"17","author":"Kiosses","year":"1997","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2021042608362834200_DEV135392C19","doi-asserted-by":"publisher","first-page":"3088","DOI":"10.1002\/dvdy.21343","article-title":"The Tol2kit: a multisite gateway-based construction kit for Tol2 transposon transgenesis constructs","volume":"236","author":"Kwan","year":"2007","journal-title":"Dev. Dyn."},{"key":"2021042608362834200_DEV135392C20","doi-asserted-by":"publisher","first-page":"4495","DOI":"10.1182\/blood.V100.13.4495","article-title":"Activin receptor-like kinase 1 is implicated in the maturation phase of angiogenesis","volume":"100","author":"Lamouille","year":"2002","journal-title":"Blood"},{"key":"2021042608362834200_DEV135392C21","doi-asserted-by":"publisher","first-page":"3403","DOI":"10.1242\/dev.095307","article-title":"Circulating Bmp10 acts through endothelial Alk1 to mediate flow-dependent arterial quiescence","volume":"140","author":"Laux","year":"2013","journal-title":"Development"},{"key":"2021042608362834200_DEV135392C22","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/labinvest.2008.112","article-title":"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","volume":"89","author":"Mahmoud","year":"2009","journal-title":"Lab. Invest."},{"key":"2021042608362834200_DEV135392C23","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":"2021042608362834200_DEV135392C24","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1161\/01.RES.0000216595.15868.55","article-title":"Shear stress regulates forward and reverse planar cell polarity of vascular endothelium in vivo and in vitro","volume":"98","author":"McCue","year":"2006","journal-title":"Circ. Res."},{"key":"2021042608362834200_DEV135392C25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fgene.2015.00001","article-title":"Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era","volume":"6","author":"McDonald","year":"2015","journal-title":"Front. Genet."},{"key":"2021042608362834200_DEV135392C26","doi-asserted-by":"publisher","first-page":"3487","DOI":"10.1172\/jci39482","article-title":"Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia","volume":"119","author":"Park","year":"2009","journal-title":"J. Clin. Invest."},{"key":"2021042608362834200_DEV135392C27","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1152\/physiol.00012.2014","article-title":"Making microvascular networks work: angiogenesis, remodeling, and pruning","volume":"29","author":"Pries","year":"2014","journal-title":"Physiology"},{"key":"2021042608362834200_DEV135392C28","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/nrc2895","article-title":"The shunt problem: control of functional shunting in normal and tumour vasculature","volume":"10","author":"Pries","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"2021042608362834200_DEV135392C29","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.ydbio.2010.08.036","article-title":"Cranial vasculature in zebrafish forms by angioblast cluster-derived angiogenesis","volume":"348","author":"Proulx","year":"2010","journal-title":"Dev. Biol."},{"key":"2021042608362834200_DEV135392C30","doi-asserted-by":"publisher","first-page":"6162","DOI":"10.1182\/blood-2012-01-407593","article-title":"BMP9 and BMP10 are critical for postnatal retinal vascular remodeling","volume":"119","author":"Ricard","year":"2012","journal-title":"Blood"},{"key":"2021042608362834200_DEV135392C31","doi-asserted-by":"publisher","first-page":"1704","DOI":"10.1126\/science.1092053","article-title":"Cell migration: integrating signals from front to back","volume":"302","author":"Ridley","year":"2003","journal-title":"Science"},{"key":"2021042608362834200_DEV135392C32","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1093\/cvr\/cvv148","article-title":"Context-specific interactions between Notch and ALK1 cannot explain ALK1-associated arteriovenous malformations","volume":"107","author":"Rochon","year":"2015","journal-title":"Cardiovasc. Res."},{"key":"2021042608362834200_DEV135392C33","first-page":"650","article-title":"Comparison of the cytoskeleton in aortic endothelial cells in situ and in vitro","volume":"49","author":"Rogers","year":"1983","journal-title":"Lab. Invest."},{"key":"2021042608362834200_DEV135392C34","doi-asserted-by":"crossref","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":"2021042608362834200_DEV135392C35","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1016\/j.mod.2009.06.1080","article-title":"Characterization of vascular mural cells during zebrafish development","volume":"126","author":"Santoro","year":"2009","journal-title":"Mech. Dev."},{"key":"2021042608362834200_DEV135392C36","doi-asserted-by":"publisher","first-page":"e12674","DOI":"10.1371\/journal.pone.0012674","article-title":"Dynamic analysis of vascular morphogenesis using transgenic quail embryos","volume":"5","author":"Sato","year":"2010","journal-title":"PloS ONE"},{"key":"2021042608362834200_DEV135392C37","doi-asserted-by":"publisher","first-page":"3103","DOI":"10.1242\/dev.112003","article-title":"Out with the old, in with the new: reassessing morpholino knockdowns in light of genome editing technology","volume":"141","author":"Schulte-Merker","year":"2014","journal-title":"Development"},{"key":"2021042608362834200_DEV135392C38","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/ng875","article-title":"Cardiac troponin T is essential in sarcomere assembly and cardiac contractility","volume":"31","author":"Sehnert","year":"2002","journal-title":"Nat. Genet."},{"key":"2021042608362834200_DEV135392C39","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1161\/01.RES.0000095246.40391.3B","article-title":"Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling","volume":"93","author":"Seki","year":"2003","journal-title":"Circ. Res."},{"key":"2021042608362834200_DEV135392C40","doi-asserted-by":"publisher","first-page":"9462","DOI":"10.1073\/pnas.142224299","article-title":"VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells","volume":"99","author":"Shay-Salit","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608362834200_DEV135392C41","doi-asserted-by":"publisher","first-page":"20812","DOI":"10.1073\/pnas.0906464106","article-title":"Illuminating cell-cycle progression in the developing zebrafish embryo","volume":"106","author":"Sugiyama","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042608362834200_DEV135392C42","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":"2021042608362834200_DEV135392C43","doi-asserted-by":"publisher","first-page":"4041","DOI":"10.1242\/dev.096255","article-title":"Dynamic responses of endothelial cells to changes in blood flow during vascular remodeling of the mouse yolk sac","volume":"140","author":"Udan","year":"2013","journal-title":"Development"},{"key":"2021042608362834200_DEV135392C44","doi-asserted-by":"publisher","first-page":"3077","DOI":"10.1002\/dvdy.21354","article-title":"Gateway compatible vectors for analysis of gene function in the zebrafish","volume":"236","author":"Villefranc","year":"2007","journal-title":"Dev. Dyn."},{"key":"2021042608362834200_DEV135392C45","doi-asserted-by":"publisher","first-page":"3119","DOI":"10.1242\/dev.048785","article-title":"Moesin1 and Ve-cadherin are required in endothelial cells during in vivo tubulogenesis","volume":"137","author":"Wang","year":"2010","journal-title":"Development"},{"key":"2021042608362834200_DEV135392C46","doi-asserted-by":"publisher","first-page":"e90590","DOI":"10.1371\/journal.pone.0090590","article-title":"An alpha-smooth muscle actin (acta2\/alphasma) zebrafish transgenic line marking vascular mural cells and visceral smooth muscle cells","volume":"9","author":"Whitesell","year":"2014","journal-title":"PLoS ONE"},{"key":"2021042608362834200_DEV135392C47","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.devcel.2011.06.033","article-title":"Semaphorin-PlexinD1 signaling limits angiogenic potential via the VEGF decoy receptor sFlt1","volume":"21","author":"Zygmunt","year":"2011","journal-title":"Dev. Cell"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/dev.135392","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/143\/14\/2593\/1843113\/dev135392.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.135392\/2052047\/dev_135392v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.135392\/2052047\/dev_135392v1.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T13:11:53Z","timestamp":1621343513000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/doi\/10.1242\/dev.135392\/263967\/Alk1-controls-arterial-endothelial-cell-migration"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,1]]},"references-count":47,"URL":"https:\/\/doi.org\/10.1242\/dev.135392","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.726416242.793562744","asserted-by":"object"}]},"ISSN":["1477-9129","0950-1991"],"issn-type":[{"value":"1477-9129","type":"electronic"},{"value":"0950-1991","type":"print"}],"subject":[],"published":{"date-parts":[[2016,1,1]]},"article-number":"dev.135392"}}