{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:41:53Z","timestamp":1790649713790,"version":"4.1.0"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"17","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,4,23]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular disorder caused by heterozygous, loss-of-function mutations in 4 transforming growth factor beta (TGF\u03b2) pathway members, including the central transcriptional mediator of the TGF\u03b2 pathway, Smad4. Loss of Smad4 causes the formation of inappropriate, fragile connections between arteries and veins called arteriovenous malformations (AVMs), which can hemorrhage leading to stroke, aneurysm, or death. Unfortunately, the molecular mechanisms underlying AVM pathogenesis remain poorly understood, and the TGF\u03b2 downstream effectors responsible for hereditary hemorrhagic telangiectasia\u2013associated AVM formation are currently unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              To identify potential biological targets of the TGF\u03b2 pathway involved in AVM formation, we performed RNA- and chromatin immunoprecipitation\u2013sequencing experiments on BMP9 (bone morphogenetic protein 9)-stimulated endothelial cells (ECs) and isolated ECs from a Smad4-inducible, EC-specific knockout (\n              <jats:italic>Smad4<\/jats:italic>\n              -iECKO) mouse model that develops retinal AVMs. These sequencing studies identified the angiopoietin-Tek signaling pathway as a downstream target of SMAD4. We used monoclonal blocking antibodies to target a specific component in this pathway and assess its effects on AVM development.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Sequencing studies uncovered 212 potential biological targets involved in AVM formation, including the EC surface receptor, TEK (TEK receptor tyrosine kinase) and its antagonistic ligand, ANGPT2 (angiopoietin-2). In\n              <jats:italic>Smad4<\/jats:italic>\n              -iECKO mice,\n              <jats:italic>Angpt2<\/jats:italic>\n              expression is robustly increased, whereas\n              <jats:italic>Tek<\/jats:italic>\n              levels are decreased, resulting in an overall reduction in angiopoietin-Tek signaling. We provide evidence that SMAD4 directly represses\n              <jats:italic>Angpt2<\/jats:italic>\n              transcription in ECs. Inhibition of ANGPT2 function in\n              <jats:italic>Smad4<\/jats:italic>\n              -deficient mice, either before or after AVMs form, prevents and alleviates AVM formation and normalizes vessel diameters. These rescue effects are attributed to a reversion in EC morphological changes, such as cell size and shape that are altered in the absence of\n              <jats:italic>Smad4.<\/jats:italic>\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              Our studies provide a novel mechanism whereby the loss of\n              <jats:italic>Smad4<\/jats:italic>\n              causes increased\n              <jats:italic>Angpt2<\/jats:italic>\n              transcription in ECs leading to AVM formation, increased blood vessel calibers, and changes in EC morphology in the retina. Blockade of ANGPT2 function in an in vivo Smad4 model of hereditary hemorrhagic telangiectasia alleviated these vascular phenotypes, further implicating ANGPT2 as an important TGF\u03b2 downstream mediator of AVM formation. Therefore, alternative approaches that target ANGPT2 function may have therapeutic value for the alleviation of hereditary hemorrhagic telangiectasia symptoms, such as AVMs.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.118.036952","type":"journal-article","created":{"date-parts":[[2019,2,12]],"date-time":"2019-02-12T10:07:31Z","timestamp":1549966051000},"page":"2049-2063","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":100,"title":["Angiopoietin-2 Inhibition Rescues Arteriovenous Malformation in a Smad4 Hereditary Hemorrhagic Telangiectasia Mouse Model"],"prefix":"10.1161","volume":"139","author":[{"given":"Angela M.","family":"Crist","sequence":"first","affiliation":[{"name":"Cell and Molecular Biology Department, Tulane University, New Orleans, LA (A.M.C., X.Z., A.R.L., S.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology Department, Tulane University, New Orleans, LA (A.M.C., X.Z., A.R.L., S.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jone","family":"Garai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans (J.G., J.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda R.","family":"Lee","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology Department, Tulane University, New Orleans, LA (A.M.C., X.Z., A.R.L., S.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janina","family":"Thoele","sequence":"additional","affiliation":[{"name":"Roche Innovation Center, Basel, Switzerland (J.T., C.U.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Ullmer","sequence":"additional","affiliation":[{"name":"Roche Innovation Center, Basel, Switzerland (J.T., C.U.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Klein","sequence":"additional","affiliation":[{"name":"Roche Innovation Center, Zurich, Switzerland (C.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jovanny","family":"Zabaleta","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans (J.G., J.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stryder M.","family":"Meadows","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology Department, Tulane University, New Orleans, LA (A.M.C., X.Z., A.R.L., S.M.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2015.00001"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/lary.25604"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0294-197"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0696-189"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1294-345"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)15732-2"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2006.041517"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2013.07.004"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1350705"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.211037"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0098646"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms13650"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063138"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.303984"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.111.647024"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3528"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.060467"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.135392"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.095307"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31101"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.028712"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10456-018-9602-0"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3534"},{"key":"e_1_3_4_25_2","first-page":"77","article-title":"Hereditary h\u00e6morrhagic telangiectasia, with report of three families and a review of those previously recorded.","volume":"32","author":"Steiner WR","year":"1916","unstructured":"Steiner, WR. Hereditary h\u00e6morrhagic telangiectasia, with report of three families and a review of those previously recorded. Trans Am Climatol Clin Assoc. 1916;32:77\u201394.","journal-title":"Trans Am Climatol Clin Assoc"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/1523-1747.ep12555569"},{"key":"e_1_3_4_27_2","first-page":"818","article-title":"Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-beta1 as well as high ALK1 tissue expression.","volume":"90","author":"Sadick H","year":"2005","unstructured":"Sadick, H, Riedel, F, Naim, R, Goessler, U, H\u00f6rmann, K, Hafner, M, Lux, A. Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-beta1 as well as high ALK1 tissue expression. Haematologica. 2005;90:818\u2013828.","journal-title":"Haematologica"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2010.07.001"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1215\/S1152851705000232"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2015.00037"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2639"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1159\/000348327"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2009.193"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.07.034"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09002"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/gene.10029"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gep.2017.01.002"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.118.033842"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep37366"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2015.00025"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.05.011"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.002949"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr500"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI58832"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.000679"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201505889"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2017.06.059"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.150904"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00577-07"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1097\/00006123-200010000-00022"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1161\/hh1401.094281"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cca.2009.12.023"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddm069"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201603106"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0088511"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39482"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-1775"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1221"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aad9260"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.10.018"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.118.036952","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T08:01:15Z","timestamp":1715587275000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.118.036952"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,23]]},"references-count":59,"journal-issue":{"issue":"17","published-print":{"date-parts":[[2019,4,23]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.118.036952"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.118.036952","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,23]]},"assertion":[{"value":"2018-07-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-01-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-02-12","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}