{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T07:39:50Z","timestamp":1779262790908,"version":"3.51.4"},"reference-count":50,"publisher":"Elsevier BV","issue":"11","license":[{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T00:00:00Z","timestamp":1698796800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2023,6,17]],"date-time":"2023-06-17T00:00:00Z","timestamp":1686960000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000615","name":"Fight for Sight UK","doi-asserted-by":"publisher","award":["MR\/K003003\/1"],"award-info":[{"award-number":["MR\/K003003\/1"]}],"id":[{"id":"10.13039\/501100000615","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ajp.amjpathol.org","clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["The American Journal of Pathology"],"published-print":{"date-parts":[[2023,11]]},"DOI":"10.1016\/j.ajpath.2023.05.017","type":"journal-article","created":{"date-parts":[[2023,6,16]],"date-time":"2023-06-16T03:06:27Z","timestamp":1686884787000},"page":"1694-1705","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":2,"title":["Role of HIF1\u03b1 and HIF2\u03b1 in Cre Recombinase\u2013Induced Retinal Pigment Epithelium Pathology and Its Secondary Effect on Choroidal Neovascularization"],"prefix":"10.1016","volume":"193","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5454-1553","authenticated-orcid":false,"given":"Enrico","family":"Cristante","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sidath E.","family":"Liyanage","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander J.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin R.","family":"Ali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James W.B.","family":"Bainbridge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.ajpath.2023.05.017_bib1","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1152\/physrev.00021.2004","article-title":"The retinal pigment epithelium in visual function","volume":"85","author":"Strauss","year":"2005","journal-title":"Physiol Rev"},{"key":"10.1016\/j.ajpath.2023.05.017_bib2","doi-asserted-by":"crossref","first-page":"802","DOI":"10.2174\/156652410793937813","article-title":"The retinal pigment epithelium in health and disease","volume":"10","author":"Sparrow","year":"2010","journal-title":"Curr Mol Med"},{"key":"10.1016\/j.ajpath.2023.05.017_bib3","first-page":"277","article-title":"Regulation of choroid development by the retinal pigment epithelium","volume":"7","author":"Zhao","year":"2001","journal-title":"Mol Vis"},{"key":"10.1016\/j.ajpath.2023.05.017_bib4","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1016\/S0002-9440(10)61231-X","article-title":"Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function","volume":"167","author":"Marneros","year":"2005","journal-title":"Am J Pathol"},{"key":"10.1016\/j.ajpath.2023.05.017_bib5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1749-6632.1998.tb10102.x","article-title":"Morphogenesis of the retinal pigment epithelium: toward understanding retinal degenerative diseases","volume":"857","author":"Marmorstein","year":"1998","journal-title":"Ann N Y Acad Sci"},{"key":"10.1016\/j.ajpath.2023.05.017_bib6","doi-asserted-by":"crossref","first-page":"413","DOI":"10.2147\/OPTH.S2151","article-title":"Age and disease-related structural changes in the retinal pigment epithelium","volume":"2","author":"Bonilha","year":"2008","journal-title":"Clin Ophthalmol"},{"key":"10.1016\/j.ajpath.2023.05.017_bib7","first-page":"1986","article-title":"Quantifying changes in RPE and choroidal vasculature in eyes with age-related macular degeneration","volume":"43","author":"Mcleod","year":"2002","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"10.1016\/j.ajpath.2023.05.017_bib8","doi-asserted-by":"crossref","first-page":"147","DOI":"10.5625\/lar.2018.34.4.147","article-title":"Mouse Cre-LoxP system: general principles to determine tissue-specific roles of target genes","volume":"34","author":"Kim","year":"2018","journal-title":"Lab Anim Res"},{"key":"10.1016\/j.ajpath.2023.05.017_bib9","first-page":"1384","article-title":"Site-specific somatic mutagenesis in the retinal pigment epithelium","volume":"43","author":"Mori","year":"2002","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"10.1016\/j.ajpath.2023.05.017_bib10","doi-asserted-by":"crossref","DOI":"10.1242\/dev.157511","article-title":"Late neuroprogenitors contribute to normal retinal vascular development in a Hif2a-dependent manner","volume":"145","author":"Cristante","year":"2018","journal-title":"Development"},{"key":"10.1016\/j.ajpath.2023.05.017_bib11","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1016\/j.ajpath.2012.01.017","article-title":"Evidence for baseline retinal pigment epithelium pathology in the Trp1-Cre mouse","volume":"180","author":"Thanos","year":"2012","journal-title":"Am J Pathol"},{"key":"10.1016\/j.ajpath.2023.05.017_bib12","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0378-1119(00)00008-1","article-title":"Mammalian genomes contain active recombinase recognition sites","volume":"244","author":"Thyagarajan","year":"2000","journal-title":"Gene"},{"key":"10.1016\/j.ajpath.2023.05.017_bib13","doi-asserted-by":"crossref","first-page":"9209","DOI":"10.1073\/pnas.161269798","article-title":"Growth inhibition and DNA damage induced by Cre recombinase in mammalian cells","volume":"98","author":"Loonstra","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.ajpath.2023.05.017_bib14","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1152\/physiolgenomics.00019.2007","article-title":"Toxicity of ligand-dependent Cre recombinases and generation of a conditional Cre deleter mouse allowing mosaic recombination in peripheral tissues","volume":"31","author":"Hameyer","year":"2007","journal-title":"Physiol Genomics"},{"key":"10.1016\/j.ajpath.2023.05.017_bib15","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.molcel.2010.09.022","article-title":"Hypoxia-inducible factors and the response to hypoxic stress","volume":"40","author":"Majmundar","year":"2010","journal-title":"Mol Cell"},{"key":"10.1016\/j.ajpath.2023.05.017_bib16","doi-asserted-by":"crossref","first-page":"9361","DOI":"10.1128\/MCB.23.24.9361-9374.2003","article-title":"Differential roles of hypoxia-inducible factor 1 alpha (HIF-1 alpha) and HIF-2 alpha in hypoxic gene regulation","volume":"23","author":"Hu","year":"2003","journal-title":"Mol Cell Biol"},{"key":"10.1016\/j.ajpath.2023.05.017_bib17","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1038\/sj.gt.3301574","article-title":"In\u00a0vivo gene transfer to the mouse eye using an HIV-based lentiviral vector; efficient long-term transduction of corneal endothelium and retinal pigment epithelium","volume":"8","author":"Bainbridge","year":"2001","journal-title":"Gene Ther"},{"key":"10.1016\/j.ajpath.2023.05.017_bib18","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/978-3-319-75402-4_22","article-title":"The role of hypoxia, hypoxia-inducible factor (HIF), and VEGF in retinal angiomatous proliferation","volume":"1074","author":"Barben","year":"2018","journal-title":"Adv Exp Med Biol"},{"key":"10.1016\/j.ajpath.2023.05.017_bib19","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1007\/s00018-019-03422-9","article-title":"The role of hypoxia-inducible factors in neovascular age-related macular degeneration: a gene therapy perspective","volume":"77","author":"Mammadzada","year":"2020","journal-title":"Cell Mol Life Sci"},{"key":"10.1016\/j.ajpath.2023.05.017_bib20","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1242\/dev.070813","article-title":"Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development","volume":"139","author":"Lange","year":"2012","journal-title":"Development"},{"key":"10.1016\/j.ajpath.2023.05.017_bib21","first-page":"4010","article-title":"Advances in brief hypoxia-inducible factor-1[alpha] is a positive factor in solid tumor growth","volume":"60","author":"Ryan","year":"2000","journal-title":"Cancer Res"},{"key":"10.1016\/j.ajpath.2023.05.017_bib22","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1073\/pnas.0608382104","article-title":"Acute postnatal ablation of Hif-2a results in anemia","volume":"104","author":"Gruber","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.ajpath.2023.05.017_bib23","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1002\/dvg.20335","article-title":"A global double-fluorescent Cre reporter mouse","volume":"45","author":"Muzumdar","year":"2007","journal-title":"Genesis"},{"key":"10.1016\/j.ajpath.2023.05.017_bib24","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0035551","article-title":"Differential modulation of retinal degeneration by Ccl2 and Cx3cr1 chemokine signalling","volume":"7","author":"Luhmann","year":"2012","journal-title":"PLoS One"},{"key":"10.1016\/j.ajpath.2023.05.017_bib25","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1038\/nprot.2010.113","article-title":"Inducible gene targeting in the neonatal vasculature and analysis of retinal angiogenesis in mice","volume":"5","author":"Pitulescu","year":"2010","journal-title":"Nat Protoc"},{"key":"10.1016\/j.ajpath.2023.05.017_bib26","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1016\/j.neurobiolaging.2015.05.019","article-title":"Cd59a deficiency in mice leads to preferential innate immune activation in the retinal pigment epithelium-choroid with age","volume":"36","author":"Herrmann","year":"2015","journal-title":"Neurobiol Aging"},{"key":"10.1016\/j.ajpath.2023.05.017_bib27","doi-asserted-by":"crossref","DOI":"10.1371\/annotation\/c6b85ec4-996d-4daf-863a-44260a888470","article-title":"Choroid sprouting assay: an ex\u00a0vivo model of microvascular angiogenesis","volume":"8","author":"Shao","year":"2013","journal-title":"PLoS One"},{"key":"10.1016\/j.ajpath.2023.05.017_bib28","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.tig.2017.12.008","article-title":"Detecting and avoiding problems when using the Cre\/lox system","volume":"34","author":"Song","year":"2018","journal-title":"Trends Genet"},{"key":"10.1016\/j.ajpath.2023.05.017_bib29","doi-asserted-by":"crossref","first-page":"4213","DOI":"10.1172\/JCI65157","article-title":"Brief report targeted deletion of Vegfa in adult mice induces vision loss","volume":"122","author":"Kurihara","year":"2012","journal-title":"J Clin Invest"},{"key":"10.1016\/j.ajpath.2023.05.017_bib30","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.mam.2012.04.005","article-title":"Understanding age-related macular degeneration (AMD): relationships between the photoreceptor\/retinal pigment epithelium\/Bruch's membrane\/choriocapillaris complex Imran","volume":"33","author":"Bhutto","year":"2012","journal-title":"Mol Aspect Med"},{"key":"10.1016\/j.ajpath.2023.05.017_bib31","first-page":"609","article-title":"Oxygen(es) and the hypoxia-inducible factor-1","volume":"7","author":"Wenger","year":"1997","journal-title":"Biol Chem"},{"key":"10.1016\/j.ajpath.2023.05.017_bib32","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1101\/gad.1243304","article-title":"The biology of hypoxia: the role of oxygen sensing in development, normal function, and disease","volume":"18","author":"Giaccia","year":"2004","journal-title":"Genes Dev"},{"key":"10.1016\/j.ajpath.2023.05.017_bib33","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/S0161-6420(02)01756-6","article-title":"Fundus autofluorescence in age-related macular degeneration","volume":"110","author":"Spaide","year":"2003","journal-title":"Ophthalmology"},{"key":"10.1016\/j.ajpath.2023.05.017_bib34","doi-asserted-by":"crossref","first-page":"5190","DOI":"10.1167\/iovs.12-9672","article-title":"Fundus autofluorescence findings in a mouse model of retinal detachment","volume":"53","author":"Secondi","year":"2012","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"10.1016\/j.ajpath.2023.05.017_bib35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0011103","article-title":"HIF-1alpha and HIF-2alpha are differentially activated in distinct cell populations in retinal ischaemia","volume":"5","author":"Mowat","year":"2010","journal-title":"PLoS One"},{"issue":"Suppl 1","key":"10.1016\/j.ajpath.2023.05.017_bib36","doi-asserted-by":"crossref","first-page":"S26","DOI":"10.1097\/IAE.0000000000001330","article-title":"Visualizing retinal pigment epithelium phenotypes in the transition to atrophy in neovascular age-related macular degeneration","volume":"36","author":"Zanzottera","year":"2016","journal-title":"Retina"},{"key":"10.1016\/j.ajpath.2023.05.017_bib37","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.14319","article-title":"Hypoxia-induced metabolic stress in retinal pigment epithelial cells is sufficient to induce photoreceptor degeneration","volume":"5","author":"Kurihara","year":"2016","journal-title":"Elife"},{"key":"10.1016\/j.ajpath.2023.05.017_bib38","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/ng1266","article-title":"Multiple organ pathology, metabolic abnormalities and impaired homeostasis of reactive oxygen species in Epas1-\/- mice","volume":"35","author":"Scortegagna","year":"2003","journal-title":"Nat Genet"},{"key":"10.1016\/j.ajpath.2023.05.017_bib39","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1016\/j.ajpath.2014.02.007","article-title":"Age- and gene-dosage-dependent Cre-induced abnormalities in the retinal pigment epithelium","volume":"184","author":"He","year":"2014","journal-title":"Am J Pathol"},{"key":"10.1016\/j.ajpath.2023.05.017_bib40","doi-asserted-by":"crossref","first-page":"13702","DOI":"10.1073\/pnas.240471297","article-title":"Illegitimate Cre-dependent chromosome rearrangements in transgenic mouse spermatids","volume":"97","author":"Schmidt","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10.1016\/j.ajpath.2023.05.017_bib41","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/j.molcel.2005.02.015","article-title":"HIF-1[alpha] induces genetic instability by transcriptionally downregulating MutS[alpha] expression","volume":"17","author":"Koshiji","year":"2005","journal-title":"Mol Cell"},{"key":"10.1016\/j.ajpath.2023.05.017_bib42","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1091\/mbc.E14-07-1194","article-title":"HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity","volume":"26","author":"Saeedi","year":"2015","journal-title":"Mol Biol Cell"},{"issue":"Suppl 3","key":"10.1016\/j.ajpath.2023.05.017_bib43","doi-asserted-by":"crossref","first-page":"S233","DOI":"10.1513\/AnnalsATS.201608-610MG","article-title":"Epithelial barrier regulation by hypoxia-inducible factor","volume":"14","author":"Glover","year":"2017","journal-title":"Ann Am Thorac Soc"},{"key":"10.1016\/j.ajpath.2023.05.017_bib44","doi-asserted-by":"crossref","first-page":"565","DOI":"10.4049\/jimmunol.1600342","article-title":"Inverse correlation between IL-10 and HIF-1[alpha] in macrophages infected\u00a0with histoplasma capsulatum","volume":"197","author":"Fecher","year":"2016","journal-title":"J Immunol"},{"key":"10.1016\/j.ajpath.2023.05.017_bib45","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/s41467-017-02683-x","article-title":"Hypoxia-inducible factor-1[alpha] is a critical transcription factor for IL-10-producing B cells in autoimmune disease","volume":"9","author":"Meng","year":"2018","journal-title":"Nat Commun"},{"key":"10.1016\/j.ajpath.2023.05.017_bib46","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/mi.2013.29","article-title":"Contribution of epithelial innate immunity to systemic protection afforded by prolyl hydroxylase inhibition in murine colitis","volume":"7","author":"Keely","year":"2014","journal-title":"Mucosal Immunol"},{"key":"10.1016\/j.ajpath.2023.05.017_bib47","first-page":"105","article-title":"Hypoxia-inducible factors as essential regulators of inflammation","volume":"345","author":"Imtiyaz","year":"2010","journal-title":"Curr Top Microbiol Immunol"},{"key":"10.1016\/j.ajpath.2023.05.017_bib48","first-page":"1","article-title":"A mouse model for laser-induced choroidal neovascularization","volume":"2015","author":"Shah","year":"2015","journal-title":"J Vis Exp"},{"key":"10.1016\/j.ajpath.2023.05.017_bib49","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1007\/s00417-009-1133-3","article-title":"Expression of hypoxia-inducible factor-1[alpha] and -2[alpha] in human choroidal neovascular membranes","volume":"247","author":"Sheridan","year":"2009","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"key":"10.1016\/j.ajpath.2023.05.017_bib50","doi-asserted-by":"crossref","first-page":"919","DOI":"10.2174\/13894501113149990015","article-title":"Hypoxia-inducible factor-1 (HIF-1): a potential target for intervention in ocular neovascular diseases","volume":"14","author":"Vadlapatla","year":"2013","journal-title":"Curr Drug Targets"}],"container-title":["The American Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0002944023002109?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0002944023002109?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T11:10:05Z","timestamp":1762081805000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0002944023002109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11]]},"references-count":50,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["S0002944023002109"],"URL":"https:\/\/doi.org\/10.1016\/j.ajpath.2023.05.017","relation":{},"ISSN":["0002-9440"],"issn-type":[{"value":"0002-9440","type":"print"}],"subject":[],"published":{"date-parts":[[2023,11]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Role of HIF1\u03b1 and HIF2\u03b1 in Cre Recombinase\u2013Induced Retinal Pigment Epithelium Pathology and Its Secondary Effect on Choroidal Neovascularization","name":"articletitle","label":"Article Title"},{"value":"The American Journal of Pathology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ajpath.2023.05.017","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2023 American Society for Investigative Pathology. Published by Elsevier Inc.","name":"copyright","label":"Copyright"}]}}