{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:27:10Z","timestamp":1791210430134,"version":"4.1.0"},"reference-count":80,"publisher":"Rockefeller University Press","issue":"1","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,1,12]]},"abstract":"<jats:p>Mutations in bone morphogenetic protein (BMP) receptor II (BMPRII) are associated with pulmonary artery endothelial cell (PAEC) apoptosis and the loss of small vessels seen in idiopathic pulmonary arterial hypertension. Given the low penetrance of BMPRII mutations, abnormalities in other converging signaling pathways may be necessary for disease development. We hypothesized that BMPRII supports normal PAEC function by recruiting Wingless (Wnt) signaling pathways to promote proliferation, survival, and motility. In this study, we report that BMP-2, via BMPRII-mediated inhibition of GSK3-\u03b2, induces \u03b2-catenin (\u03b2-C) accumulation and transcriptional activity necessary for PAEC survival and proliferation. At the same time, BMP-2 mediates phosphorylated Smad1 (pSmad1) or, with loss of BMPRII, pSmad3-dependent recruitment of Disheveled (Dvl) to promote RhoA\u2013Rac1 signaling necessary for motility. Finally, using an angiogenesis assay in severe combined immunodeficient mice, we demonstrate that both \u03b2-C\u2013 and Dvl-mediated RhoA\u2013Rac1 activation are necessary for vascular growth in vivo. These findings suggest that the recruitment of both canonical and noncanonical Wnt pathways is required in BMP-2\u2013mediated angiogenesis.<\/jats:p>","DOI":"10.1083\/jcb.200806049","type":"journal-article","created":{"date-parts":[[2009,1,12]],"date-time":"2009-01-12T19:23:22Z","timestamp":1231788202000},"page":"83-99","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":206,"title":["Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt\u2013\u03b2-catenin and Wnt\u2013RhoA\u2013Rac1 pathways"],"prefix":"10.1083","volume":"184","author":[{"given":"Vinicio A.","family":"de Jesus Perez","sequence":"first","affiliation":[{"name":"1Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tero-Pekka","family":"Alastalo","sequence":"additional","affiliation":[{"name":"3Department of Pediatrics, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny C.","family":"Wu","sequence":"additional","affiliation":[{"name":"1Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey D.","family":"Axelrod","sequence":"additional","affiliation":[{"name":"2Department of Pathology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Cooke","sequence":"additional","affiliation":[{"name":"1Department of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Amieva","sequence":"additional","affiliation":[{"name":"3Department of Pediatrics, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Rabinovitch","sequence":"additional","affiliation":[{"name":"3Department of Pediatrics, Stanford University, Stanford, CA 94305"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2009,1,12]]},"reference":[{"key":"2023072220385247600_BIB1","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/nrm2183","volume":"8","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023072220385247600_BIB2","doi-asserted-by":"crossref","first-page":"615","DOI":"10.2353\/ajpath.2008.070705","volume":"172","year":"2008","journal-title":"Am. J. Pathol."},{"key":"2023072220385247600_BIB3","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1126\/science.1071809","volume":"296","year":"2002","journal-title":"Science."},{"key":"2023072220385247600_BIB4","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1100\/tsw.2002.105","volume":"2","year":"2002","journal-title":"ScientificWorldJournal."},{"key":"2023072220385247600_BIB5","doi-asserted-by":"crossref","first-page":"2610","DOI":"10.1101\/gad.12.16.2610","volume":"12","year":"1998","journal-title":"Genes Dev."},{"key":"2023072220385247600_BIB6","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/S0006-291X(02)02951-0","volume":"301","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2023072220385247600_BIB7","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1006\/dbio.2000.9670","volume":"221","year":"2000","journal-title":"Dev. Biol."},{"key":"2023072220385247600_BIB8","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/S0092-8674(00)81226-X","volume":"94","year":"1998","journal-title":"Cell."},{"key":"2023072220385247600_BIB9","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1038\/nature01056","volume":"419","year":"2002","journal-title":"Nature."},{"key":"2023072220385247600_BIB10","doi-asserted-by":"crossref","first-page":"L1033","DOI":"10.1152\/ajplung.00277.2004","volume":"288","year":"2005","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2023072220385247600_BIB11","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/35096075","volume":"2","year":"2001","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023072220385247600_BIB12","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1159\/000103205","volume":"74","year":"2007","journal-title":"Respiration."},{"key":"2023072220385247600_BIB13","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s00776-004-0815-2","volume":"9","year":"2004","journal-title":"J. Orthop. Sci."},{"key":"2023072220385247600_BIB14","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1210\/endo.143.4.8719","volume":"143","year":"2002","journal-title":"Endocrinology."},{"key":"2023072220385247600_BIB15","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1086\/303059","volume":"67","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"2023072220385247600_BIB16","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.molcel.2005.06.009","volume":"19","year":"2005","journal-title":"Mol. Cell."},{"key":"2023072220385247600_BIB17","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1074\/jbc.M406391200","volume":"280","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2023072220385247600_BIB18","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1002\/jcb.10091","volume":"84","year":"2002","journal-title":"J. Cell. Biochem."},{"key":"2023072220385247600_BIB19","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1083\/jcb.200212060","volume":"162","year":"2003","journal-title":"J. Cell Biol."},{"key":"2023072220385247600_BIB20","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/34848","volume":"391","year":"1998","journal-title":"Nature."},{"key":"2023072220385247600_BIB21","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1101\/gad.1022203","volume":"17","year":"2003","journal-title":"Genes Dev."},{"key":"2023072220385247600_BIB22","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1161\/CIRCULATIONAHA.106.663120","volume":"115","year":"2007","journal-title":"Circulation."},{"key":"2023072220385247600_BIB23","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1126\/science.281.5382.1509","volume":"281","year":"1998","journal-title":"Science."},{"key":"2023072220385247600_BIB24","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1242\/dev.01573","volume":"132","year":"2005","journal-title":"Development."},{"key":"2023072220385247600_BIB25","doi-asserted-by":"crossref","first-page":"13S","DOI":"10.1016\/j.jacc.2004.02.029","volume":"43","year":"2004","journal-title":"J. Am. Coll. Cardiol."},{"key":"2023072220385247600_BIB26","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1056\/NEJMra040291","volume":"351","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"2023072220385247600_BIB27","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1242\/dev.128.1.25","volume":"128","year":"2001","journal-title":"Development."},{"key":"2023072220385247600_BIB28","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/21674","volume":"399","year":"1999","journal-title":"Nature."},{"key":"2023072220385247600_BIB29","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1128\/MCB.23.4.1379-1389.2003","volume":"23","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"2023072220385247600_BIB30","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/S1016-8478(23)17431-0","volume":"22","year":"2006","journal-title":"Mol. Cells."},{"key":"2023072220385247600_BIB31","doi-asserted-by":"crossref","first-page":"4487","DOI":"10.1128\/MCB.24.10.4487-4501.2004","volume":"24","year":"2004","journal-title":"Mol. Cell. Biol."},{"key":"2023072220385247600_BIB32","doi-asserted-by":"crossref","first-page":"8358","DOI":"10.1073\/pnas.150152697","volume":"97","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072220385247600_BIB33","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1161\/01.RES.0000259593.07661.1e","volume":"100","year":"2007","journal-title":"Circ. Res."},{"key":"2023072220385247600_BIB34","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1158\/1541-7786.141.2.3","volume":"2","year":"2004","journal-title":"Mol. Cancer Res."},{"key":"2023072220385247600_BIB35","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1074\/jbc.274.1.129","volume":"274","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2023072220385247600_BIB36","doi-asserted-by":"crossref","first-page":"17156","DOI":"10.1074\/jbc.M513812200","volume":"281","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2023072220385247600_BIB37","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1146\/annurev.cellbio.20.010403.113126","volume":"20","year":"2004","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"2023072220385247600_BIB38","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1161\/01.RES.0000215809.47923.fd","volume":"98","year":"2006","journal-title":"Circ. Res."},{"key":"2023072220385247600_BIB39","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1086\/316947","volume":"68","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"2023072220385247600_BIB40","doi-asserted-by":"crossref","first-page":"3277","DOI":"10.1093\/hmg\/ddg365","volume":"12","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"2023072220385247600_BIB41","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s10456-005-5612-9","volume":"8","year":"2005","journal-title":"Angiogenesis."},{"key":"2023072220385247600_BIB42","doi-asserted-by":"crossref","first-page":"L548","DOI":"10.1152\/ajplung.00428.2006","volume":"293","year":"2007","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2023072220385247600_BIB43","doi-asserted-by":"crossref","first-page":"2993","DOI":"10.1101\/gad.1167003","volume":"17","year":"2003","journal-title":"Genes Dev."},{"key":"2023072220385247600_BIB44","doi-asserted-by":"crossref","first-page":"3027","DOI":"10.1101\/gad.9.24.3027","volume":"9","year":"1995","journal-title":"Genes Dev."},{"key":"2023072220385247600_BIB45","doi-asserted-by":"publisher","year":"2002","journal-title":"Sci. STKE","DOI":"10.1126\/stke.2002.151.pe40"},{"key":"2023072220385247600_BIB46","doi-asserted-by":"crossref","first-page":"30957","DOI":"10.1074\/jbc.274.43.30957","volume":"274","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2023072220385247600_BIB47","doi-asserted-by":"crossref","first-page":"7713","DOI":"10.1074\/jbc.272.12.7713","volume":"272","year":"1997","journal-title":"J. Biol. Chem."},{"key":"2023072220385247600_BIB48","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1016\/0092-8674(92)90630-U","volume":"69","year":"1992","journal-title":"Cell."},{"key":"2023072220385247600_BIB49","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1126\/science.275.5307.1752","volume":"275","year":"1997","journal-title":"Science."},{"key":"2023072220385247600_BIB50","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1007\/s00432-005-0024-1","volume":"131","year":"2005","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"2023072220385247600_BIB51","doi-asserted-by":"crossref","first-page":"1842","DOI":"10.1359\/jbmr.2003.18.10.1842","volume":"18","year":"2003","journal-title":"J. Bone Miner. Res."},{"key":"2023072220385247600_BIB52","doi-asserted-by":"crossref","first-page":"216","DOI":"10.7326\/0003-4819-107-2-216","volume":"107","year":"1987","journal-title":"Ann. Intern. Med."},{"key":"2023072220385247600_BIB53","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1183\/09031936.04.00018604","volume":"24","year":"2004","journal-title":"Eur. Respir. J."},{"key":"2023072220385247600_BIB54","doi-asserted-by":"crossref","first-page":"L362","DOI":"10.1152\/ajplung.00111.2005","volume":"291","year":"2006","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2023072220385247600_BIB55","doi-asserted-by":"crossref","first-page":"35873","DOI":"10.1074\/jbc.M605343200","volume":"281","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2023072220385247600_BIB56","doi-asserted-by":"crossref","first-page":"18544","DOI":"10.1074\/jbc.M311592200","volume":"279","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2023072220385247600_BIB57","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1016\/S0002-9440(10)61110-8","volume":"160","year":"2002","journal-title":"Am. J. Pathol."},{"key":"2023072220385247600_BIB58","first-page":"253","volume":"360","year":"2007","journal-title":"Methods Mol. Biol."},{"key":"2023072220385247600_BIB59","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1161\/CIRCULATIONAHA.104.492488","volume":"112","year":"2005","journal-title":"Circulation."},{"key":"2023072220385247600_BIB60","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s00774-005-0622-7","volume":"23","year":"2005","journal-title":"J. Bone Miner. Metab."},{"key":"2023072220385247600_BIB61","doi-asserted-by":"crossref","first-page":"6209","DOI":"10.1242\/dev.00846","volume":"130","year":"2003","journal-title":"Development."},{"key":"2023072220385247600_BIB62","doi-asserted-by":"crossref","first-page":"1877","DOI":"10.1242\/dev.125.10.1877","volume":"125","year":"1998","journal-title":"Development."},{"key":"2023072220385247600_BIB63","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1161\/01.RES.0000200180.01710.e6","volume":"98","year":"2006","journal-title":"Circ. Res."},{"key":"2023072220385247600_BIB64","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/18884","volume":"398","year":"1999","journal-title":"Nature."},{"key":"2023072220385247600_BIB65","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1136\/jmg.37.10.741","volume":"37","year":"2000","journal-title":"J. Med. Genet."},{"key":"2023072220385247600_BIB66","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1126\/science.1156037","volume":"320","year":"2008","journal-title":"Science."},{"key":"2023072220385247600_BIB67","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1083\/jcb.149.7.1433","volume":"149","year":"2000","journal-title":"J. Cell Biol."},{"key":"2023072220385247600_BIB68","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1089\/152308602760598990","volume":"4","year":"2002","journal-title":"Antioxid. Redox Signal."},{"key":"2023072220385247600_BIB69","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1161\/01.ATV.21.3.300","volume":"21","year":"2001","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"2023072220385247600_BIB70","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1242\/dev.02347","volume":"133","year":"2006","journal-title":"Development."},{"key":"2023072220385247600_BIB71","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/j.1601-6343.2005.00319.x","volume":"8","year":"2005","journal-title":"Orthod. Craniofac. Res."},{"key":"2023072220385247600_BIB72","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1006\/bbrc.1999.1344","volume":"263","year":"1999","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2023072220385247600_BIB73","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1126\/science.270.5244.2008","volume":"270","year":"1995","journal-title":"Science."},{"key":"2023072220385247600_BIB74","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/31735","volume":"393","year":"1998","journal-title":"Nature."},{"key":"2023072220385247600_BIB75","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1161\/01.RES.0000166926.54293.68","volume":"96","year":"2005","journal-title":"Circ. Res."},{"key":"2023072220385247600_BIB76","doi-asserted-by":"crossref","first-page":"E2","DOI":"10.1161\/01.RES.88.1.2","volume":"88","year":"2001","journal-title":"Circ. Res."},{"key":"2023072220385247600_BIB77","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.devcel.2006.10.015","volume":"12","year":"2007","journal-title":"Dev. Cell."},{"key":"2023072220385247600_BIB78","doi-asserted-by":"crossref","first-page":"24443","DOI":"10.1074\/jbc.M502825200","volume":"280","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2023072220385247600_BIB79","first-page":"8664","volume":"61","year":"2001","journal-title":"Cancer Res."},{"key":"2023072220385247600_BIB80","first-page":"6050","volume":"61","year":"2001","journal-title":"Cancer Res."}],"container-title":["The Journal of Cell Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jcb\/article-pdf\/184\/1\/83\/1554916\/jcb_200806049.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jcb\/article-pdf\/184\/1\/83\/1554916\/jcb_200806049.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,9]],"date-time":"2024-03-09T00:09:50Z","timestamp":1709942990000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jcb\/article\/184\/1\/83\/35215\/Bone-morphogenetic-protein-2-induces-pulmonary"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,1,12]]},"references-count":80,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,1,12]]}},"URL":"https:\/\/doi.org\/10.1083\/jcb.200806049","relation":{},"ISSN":["1540-8140","0021-9525"],"issn-type":[{"value":"1540-8140","type":"electronic"},{"value":"0021-9525","type":"print"}],"subject":[],"published":{"date-parts":[[2009,1,12]]}}}