{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:25:57Z","timestamp":1790774757437,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>We determined in patients with pulmonary arterial (PA) hypertension (PAH) whether in addition to increased production of elastase by PA smooth muscle cells previously reported, PA elastic fibers are susceptible to degradation because of their abnormal assembly.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>\n              Fibrillin-1 and elastin are the major components of elastic fibers, and fibrillin-1 binds bone morphogenetic proteins (BMPs) and the large latent complex of transforming growth factor-\u03b21 (TGF\u03b21). Thus, we considered whether BMPs like TGF\u03b21 contribute to elastic fiber assembly and whether this process is perturbed in PAH particularly when the BMP receptor, BMPR2, is mutant. We also assessed whether in mice with\n              <jats:italic>Bmpr2\/1a<\/jats:italic>\n              compound heterozygosity, elastic fibers are susceptible to degradation. In PA smooth muscle cells and adventitial fibroblasts, TGF\u03b21 increased elastin mRNA, but the elevation in elastin protein was dependent on BMPR2; TGF\u03b21 and BMP4, via BMPR2, increased extracellular accumulation of fibrillin-1. Both BMP4- and TGF\u03b21-stimulated elastic fiber assembly was impaired in idiopathic (I) PAH-PA adventitial fibroblast versus control cells, particularly those with hereditary (H) PAH and a\n              <jats:italic>BMPR2<\/jats:italic>\n              mutation. This was related to profound reductions in elastin and fibrillin-1 mRNA. Elastin protein was increased in IPAH PA adventitial fibroblast by TGF\u03b21 but only minimally so in\n              <jats:italic>BMPR2<\/jats:italic>\n              mutant cells. Fibrillin-1 protein increased only modestly in IPAH or HPAH PA adventitial fibroblasts stimulated with BMP4 or TGF\u03b21. In\n              <jats:italic>Bmpr2\/1a<\/jats:italic>\n              heterozygote mice, reduced PA fibrillin-1 was associated with elastic fiber susceptibility to degradation and more severe pulmonary hypertension.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>Disrupting BMPR2 impairs TGF\u03b21- and BMP4-mediated elastic fiber assembly and is of pathophysiologic significance in PAH.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.117.309696","type":"journal-article","created":{"date-parts":[[2017,6,16]],"date-time":"2017-06-16T01:10:27Z","timestamp":1497575427000},"page":"1559-1569","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":50,"title":["Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor-\u03b2 in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension"],"prefix":"10.1161","volume":"37","author":[{"given":"Nancy F.","family":"Tojais","sequence":"first","affiliation":[{"name":"From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health &amp; Science University, Portland (L.Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiqin","family":"Cao","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health &amp; Science University, Portland (L.Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Ju","family":"Lai","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health &amp; Science University, Portland (L.Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingli","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health &amp; Science University, Portland (L.Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin-I","family":"Chen","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health &amp; Science University, Portland (L.Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel A. Alejandre","family":"Alcazar","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health &amp; Science University, Portland (L.Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinicio A.","family":"de Jesus Perez","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health &amp; Science University, Portland (L.Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel K.","family":"Hopper","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health &amp; Science University, Portland (L.Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Rhodes","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health &amp; Science University, Portland (L.Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew A.","family":"Bill","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health &amp; Science University, Portland (L.Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn Y.","family":"Sakai","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health &amp; Science University, Portland (L.Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Rabinovitch","sequence":"additional","affiliation":[{"name":"From the Department of Pediatrics (N.F.T., A.C., Y.-J.L., L.W., P.I.C., M.A.A.A., R.K.H., C.J.R., M.R.) and Department of Medicine (V.A.d.J.P., M.A.B.), the Vera Moulton Wall Center for Pulmonary Vascular Disease and the Cardiovascular Institute, Stanford University School of Medicine, CA; and Shriners Hospital for Children, Oregon Health &amp; Science University, Portland (L.Y.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/79226"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/303059"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000012754.72951.3d"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20922"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e318172dcdf"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.88.6.555"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2016.08.019"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2795(71)90237-6"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)98752-1"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1116"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707820200"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.21643"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.05.051"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199603)166:3<495::AID-JCP4>3.0.CO;2-K"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI109926"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0993-11"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/352337a0"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201201-0164OC"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(15)00544-5"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E08-08-0830"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/jor.23130"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.016133"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.060269"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201412-2291OC"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201408-1528OC"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81112-5"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2009.05.005"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0070-2153(06)79005-6"},{"issue":"19","key":"e_1_3_5_30_2","first-page":"III289","article-title":"Gene transfer of the serine elastase inhibitor elafin protects against vein graft degeneration.","volume":"102","author":"O\u2019Blenes SB","year":"2000","unstructured":"O\u2019Blenes SB, Zaidi SH, Cheah AY, McIntyre B, Kaneda Y, Rabinovitch M. Gene transfer of the serine elastase inhibitor elafin protects against vein graft degeneration. Circulation. 2000;102(19 Suppl 3):III289\u2013III295.","journal-title":"Circulation"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.11.7314"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.134270"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.10.11.3595"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1086\/302968"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1215779110"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000202051.28319.c8"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.17.1.2816"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.03.010"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117737"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.253740"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds073"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000215809.47923.fd"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00239.2004"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2012-0470OC"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201408-1464OC"}],"container-title":["Arteriosclerosis, Thrombosis, and Vascular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/ATVBAHA.117.309696","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,12]],"date-time":"2024-05-12T23:14:39Z","timestamp":1715555679000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/ATVBAHA.117.309696"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8]]},"references-count":44,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2017,8]]}},"alternative-id":["10.1161\/ATVBAHA.117.309696"],"URL":"https:\/\/doi.org\/10.1161\/atvbaha.117.309696","relation":{},"ISSN":["1079-5642","1524-4636"],"issn-type":[{"value":"1079-5642","type":"print"},{"value":"1524-4636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8]]},"assertion":[{"value":"2016-12-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-05-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-06-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}