{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T06:07:59Z","timestamp":1772604479850,"version":"3.50.1"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2019,1,22]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Hypoxia-inducible factors (HIFs), especially HIF-1\u03b1 and HIF-2\u03b1, are key mediators of the adaptive response to hypoxic stress and play essential roles in maintaining lung homeostasis. Human and animal genetics studies confirm that abnormal HIF correlates with pulmonary vascular pathology and chronic lung diseases, but it remains unclear whether endothelial cell HIF production is essential for microvascular health. The large airway has an ideal circulatory bed for evaluating histological changes and physiology in genetically modified rodents.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>The tracheal microvasculature of mice, with conditionally deleted or overexpressed HIF-1\u03b1 or HIF-2\u03b1, was evaluated for anatomy, perfusion, and permeability. Angiogenic signaling studies assessed vascular changes attributable to dysregulated HIF expression. An orthotopic tracheal transplantation model further evaluated the contribution of individual HIF isoforms in airway endothelial cells.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              The genetic deletion of\n              <jats:italic>Hif-2\u03b1<\/jats:italic>\n              but not\n              <jats:italic>Hif-1\u03b1<\/jats:italic>\n              caused tracheal endothelial cell apoptosis, diminished pericyte coverage, reduced vascular perfusion, defective barrier function, overlying epithelial abnormalities, and subepithelial fibrotic remodeling. HIF-2\u03b1 promoted microvascular integrity in airways through endothelial angiopoietin-1\/TIE2 signaling and Notch activity. In functional tracheal transplants, HIF-2\u03b1 deficiency in airway donors accelerated graft microvascular loss, whereas HIF-2\u03b1 or angiopoietin-1 overexpression prolonged transplant microvascular perfusion. Augmented endothelial HIF-2\u03b1 in transplant donors promoted airway microvascular integrity and diminished alloimmune inflammation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Our findings reveal that the constitutive expression of endothelial HIF-2\u03b1 is required for airway microvascular health.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.118.036157","type":"journal-article","created":{"date-parts":[[2019,1,17]],"date-time":"2019-01-17T13:44:06Z","timestamp":1547732646000},"page":"502-517","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":44,"title":["Endothelial Hypoxia-Inducible Factor-2\u03b1 Is Required for the Maintenance of Airway Microvasculature"],"prefix":"10.1161","volume":"139","author":[{"given":"Xinguo","family":"Jiang","sequence":"first","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., C.C., E.C.B., M.R.N.)."},{"name":"School of Medicine, Stanford University, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., A.J.G., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Tian","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., C.C., E.C.B., M.R.N.)."},{"name":"School of Medicine, Stanford University, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., A.J.G., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Allen B.","family":"Tu","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., C.C., E.C.B., M.R.N.)."},{"name":"School of Medicine, Stanford University, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., A.J.G., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shravani","family":"Pasupneti","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., C.C., E.C.B., M.R.N.)."},{"name":"School of Medicine, Stanford University, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., A.J.G., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Shuffle","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., C.C., E.C.B., M.R.N.)."},{"name":"School of Medicine, Stanford University, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., A.J.G., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Dahms","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., C.C., E.C.B., M.R.N.)."},{"name":"School of Medicine, Stanford University, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., A.J.G., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Zhang","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., C.C., E.C.B., M.R.N.)."},{"name":"School of Medicine, Stanford University, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., A.J.G., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haoliang","family":"Cai","sequence":"additional","affiliation":[{"name":"School of Information, University of Michigan, Ann Arbor (H.C.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thanh T.","family":"Dinh","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., C.C., E.C.B., M.R.N.)."},{"name":"School of Medicine, Stanford University, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., A.J.G., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Liu","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., C.C., E.C.B., M.R.N.)."},{"name":"School of Medicine, Stanford University, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., A.J.G., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corey","family":"Cain","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., C.C., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amato J.","family":"Giaccia","sequence":"additional","affiliation":[{"name":"School of Medicine, Stanford University, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., A.J.G., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eugene C.","family":"Butcher","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., C.C., E.C.B., M.R.N.)."},{"name":"School of Medicine, Stanford University, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., A.J.G., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Celeste","family":"Simon","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine, University of Pennsylvania, Philadelphia (M.C.S.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregg L.","family":"Semenza","sequence":"additional","affiliation":[{"name":"School of Medicine, Johns Hopkins University, Baltimore, MD (G.L.S.)."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark R.","family":"Nicolls","sequence":"additional","affiliation":[{"name":"Veterans Affairs Palo Alto Health Care System, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., C.C., E.C.B., M.R.N.)."},{"name":"School of Medicine, Stanford University, CA (X.J., W.T., A.B.T., S.P., E.S., P.D., P.Z., T.T.D., B.L., A.J.G., E.C.B., M.R.N.)."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-014-1173-y"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1513\/pats.201101-007MW"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00169113"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.09.022"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI5912"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI15496"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1602978113"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.021494"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01055-15"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.250167.114"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S10611"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00022910"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004898"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2003.07.003"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI46192"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2013.09.092"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.93121"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09002"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/74725"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63273-7"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.107.161521"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.07.001"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI77701"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI57322"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.192641"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24311"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI32311"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI84871"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20122709"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2012.06.004"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-12-193581"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17040"},{"key":"e_1_3_4_34_2","first-page":"1029","article-title":"Vascular permeability factor\/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.","volume":"146","author":"Dvorak HF","year":"1995","unstructured":"Dvorak, HF, Brown, LF, Detmar, M, Dvorak, AM. Vascular permeability factor\/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. 1995;146:1029\u20131039.","journal-title":"Am J Pathol"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6962"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.1.72"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-02-270819"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.108.169235"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.221449198"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20090389"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200602-304OC"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep16449"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81436-1"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/376070a0"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81813-9"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mod.2013.07.001"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1881410"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0000000000000361"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20150718"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-017-0505-1"},{"key":"e_1_3_4_51_2","first-page":"453","article-title":"Role of angiogenesis and vascular remodeling in chronic obstructive pulmonary disease.","volume":"2","author":"Siafakas NM","year":"2007","unstructured":"Siafakas, NM, Antoniou, KM, Tzortzaki, EG. Role of angiogenesis and vascular remodeling in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2007;2:453\u2013462.","journal-title":"Int J Chron Obstruct Pulmon Dis"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.118.036157","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T07:56:42Z","timestamp":1715587002000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.118.036157"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,22]]},"references-count":50,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019,1,22]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.118.036157"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.118.036157","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,22]]},"assertion":[{"value":"2018-05-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-08-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}