{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T14:24:51Z","timestamp":1790605491271,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"24","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2016,6,14]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>Vascular occlusion and complex plexiform lesions are hallmarks of the pathology of severe pulmonary arterial hypertension (PAH) in patients. However, the mechanisms of obliterative vascular remodeling remain elusive; hence, current therapies have not targeted the fundamental disease-modifying mechanisms and result in only modest improvement in morbidity and mortality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      Mice with\n                      <jats:italic>Tie2<\/jats:italic>\n                      Cre-mediated disruption of\n                      <jats:italic>Egln1<\/jats:italic>\n                      (encoding prolyl-4 hydroxylase 2 [PHD2];\n                      <jats:italic>Egln1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>Tie2<\/jats:italic>\n                      <\/jats:sup>\n                      ) in endothelial cells and hematopoietic cells exhibited spontaneous severe PAH with extensive pulmonary vascular remodeling, including vascular occlusion and plexiform-like lesions, resembling the hallmarks of the pathology of clinical PAH. As seen in patients with idiopathic PAH,\n                      <jats:italic>Egln1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>Tie2<\/jats:italic>\n                      <\/jats:sup>\n                      mice exhibited unprecedented right ventricular hypertrophy and failure and progressive mortality. Consistently, PHD2 expression was diminished in lung endothelial cells of obliterated pulmonary vessels in patients with idiopathic PAH. Genetic deletions of both\n                      <jats:italic>Egln1<\/jats:italic>\n                      and\n                      <jats:italic>Hif1a<\/jats:italic>\n                      or\n                      <jats:italic>Egln1<\/jats:italic>\n                      and\n                      <jats:italic>Hif2a<\/jats:italic>\n                      identified hypoxia-inducible factor-2\u03b1 as the critical mediator of the severe PAH seen in\n                      <jats:italic>Egln1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>Tie2<\/jats:italic>\n                      <\/jats:sup>\n                      mice. We also observed altered expression of many pulmonary hypertension\u2013causing genes in\n                      <jats:italic>Egln1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>Tie2<\/jats:italic>\n                      <\/jats:sup>\n                      lungs, which was normalized in\n                      <jats:italic>Egln1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>Tie2<\/jats:italic>\n                      <\/jats:sup>\n                      \/\n                      <jats:italic>Hif2a<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>Tie2<\/jats:italic>\n                      <\/jats:sup>\n                      lungs. PHD2-deficient endothelial cells promoted smooth muscle cell proliferation in part through hypoxia-inducible factor-2\u03b1\u2013activated CXCL12 expression. Genetic deletion of\n                      <jats:italic>Cxcl12<\/jats:italic>\n                      attenuated PAH in\n                      <jats:italic>Egln1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>Tie2<\/jats:italic>\n                      <\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>These studies defined an unexpected role of PHD2 deficiency in the mechanisms of severe PAH and identified the first genetically modified mouse model with obliterative vascular remodeling and pathophysiology recapitulating clinical PAH. Thus, targeting PHD2\/hypoxia-inducible factor-2\u03b1 signaling is a promising strategy to reverse vascular remodeling for treatment of severe PAH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.116.021494","type":"journal-article","created":{"date-parts":[[2016,6,13]],"date-time":"2016-06-13T18:28:11Z","timestamp":1465842491000},"page":"2447-2458","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":237,"title":["Prolyl-4 Hydroxylase 2 (PHD2) Deficiency in Endothelial Cells and Hematopoietic Cells Induces Obliterative Vascular Remodeling and Severe Pulmonary Arterial Hypertension in Mice and Humans Through Hypoxia-Inducible Factor-2\u03b1"],"prefix":"10.1161","volume":"133","author":[{"given":"Zhiyu","family":"Dai","sequence":"first","affiliation":[{"name":"From Department of Pharmacology (Z.D., M.L., M.M.Z., Y.-Y.Z.) and Center for Lung and Vascular Biology (Z.D., M.L., M.M.Z., Y.-Y.Z.), University of Illinois College of Medicine, Chicago; and Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College of London, Hammersmith Hospital, UK (J.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Li","sequence":"additional","affiliation":[{"name":"From Department of Pharmacology (Z.D., M.L., M.M.Z., Y.-Y.Z.) and Center for Lung and Vascular Biology (Z.D., M.L., M.M.Z., Y.-Y.Z.), University of Illinois College of Medicine, Chicago; and Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College of London, Hammersmith Hospital, UK (J.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Wharton","sequence":"additional","affiliation":[{"name":"From Department of Pharmacology (Z.D., M.L., M.M.Z., Y.-Y.Z.) and Center for Lung and Vascular Biology (Z.D., M.L., M.M.Z., Y.-Y.Z.), University of Illinois College of Medicine, Chicago; and Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College of London, Hammersmith Hospital, UK (J.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie M.","family":"Zhu","sequence":"additional","affiliation":[{"name":"From Department of Pharmacology (Z.D., M.L., M.M.Z., Y.-Y.Z.) and Center for Lung and Vascular Biology (Z.D., M.L., M.M.Z., Y.-Y.Z.), University of Illinois College of Medicine, Chicago; and Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College of London, Hammersmith Hospital, UK (J.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You-Yang","family":"Zhao","sequence":"additional","affiliation":[{"name":"From Department of Pharmacology (Z.D., M.L., M.M.Z., Y.-Y.Z.) and Center for Lung and Vascular Biology (Z.D., M.L., M.M.Z., Y.-Y.Z.), University of Illinois College of Medicine, Chicago; and Centre for Pharmacology and Therapeutics, Department of Medicine, Imperial College of London, Hammersmith Hospital, UK (J.W.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.192230"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccl.2004.04.010"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2004.02.033"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0272-5231(05)70279-3"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201201-0164OC"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.108.782979"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005428"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.03.540"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-38664-0_5"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00362.2011"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.09.022"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.01.021"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059817"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00507-4"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059796"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.305109"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201009-1393PP"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI5912"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI15496"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201302-0302OC"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-04-153718"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.444059"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030290"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI36362"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg392"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406026200"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00425-06"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-10-117812"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.701516"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43273"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000243584.45145.3f"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201103-0412OC"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1086\/678508"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.2000.0106"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI33338"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80043-4"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.172360799"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1002\/gene.1030"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.193.6.741"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0343com"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.927681"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2014-0311OC"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E06-05-0419"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.02-0445fje"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1413687"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-09-306357"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.070705"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.301141"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.050599"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-260182"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.116.021494","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T02:38:40Z","timestamp":1715567920000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.116.021494"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,14]]},"references-count":50,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2016,6,14]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.116.021494"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.116.021494","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.726330858.793519763","asserted-by":"object"}]},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,14]]},"assertion":[{"value":"2016-01-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-04-19","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-04-25","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}