{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T21:46:00Z","timestamp":1775598360357,"version":"3.50.1"},"reference-count":53,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T00:00:00Z","timestamp":1592524800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD097660"],"award-info":[{"award-number":["HD097660"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["EY028714"],"award-info":[{"award-number":["EY028714"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Retinopathy of prematurity (ROP) is the leading cause of blindness in infants. We have investigated the efficacy of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine and glycine conjugated derivatives tauroursodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA) in preventing retinal neovascularization (RNV) in an experimental model of ROP. Seven-day-old mice pups (P7) were subjected to oxygen-induced retinopathy (OIR) and were treated with bile acids for various durations. Analysis of retinal vascular growth and distribution revealed that UDCA treatment (50 mg\/kg, P7\u2013P17) of OIR mice decreased the extension of neovascular and avascular areas, whereas treatments with TUDCA and GUDCA showed no changes. UDCA also prevented reactive gliosis, preserved ganglion cell survival, and ameliorated OIR-induced blood retinal barrier dysfunction. These effects were associated with decreased levels of oxidative stress markers, inflammatory cytokines, and normalization of the VEGF\u2013STAT3 signaling axis. Furthermore, in vitro tube formation and permeability assays confirmed UDCA inhibitory activity toward VEGF-induced pro-angiogenic and pro-permeability effects on human retinal microvascular endothelial cells. Collectively, our results suggest that UDCA could represent a new effective therapy for ROP.<\/jats:p>","DOI":"10.3390\/jcm9061921","type":"journal-article","created":{"date-parts":[[2020,6,19]],"date-time":"2020-06-19T10:43:58Z","timestamp":1592563438000},"page":"1921","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Ursodeoxycholic Acid Halts Pathological Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy"],"prefix":"10.3390","volume":"9","author":[{"given":"Menaka C.","family":"Thounaojam","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1712-454X","authenticated-orcid":false,"given":"Ravirajsinh N.","family":"Jadeja","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shubhra","family":"Rajpurohit","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana R.","family":"Gutsaeva","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1105-8895","authenticated-orcid":false,"given":"Brian K.","family":"Stansfield","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Neonatal-Perinatal Medicine, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Vascular Biology Center, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pamela M.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuela","family":"Bartoli","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1007\/s00431-011-1610-7","article-title":"Educational paper: Retinopathy of prematurity","volume":"171","author":"Casteels","year":"2012","journal-title":"Eur. J. Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/aos.12049","article-title":"The pathophysiology of retinopathy of prematurity: An update of previous and recent knowledge","volume":"92","author":"Cavallaro","year":"2013","journal-title":"Acta Ophthalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"35","DOI":"10.5409\/wjcp.v5.i1.35","article-title":"Retinopathy of prematurity: Past, present and future","volume":"5","author":"Shah","year":"2016","journal-title":"World J. Clin. Pediatr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1136\/bjo.84.2.138","article-title":"Long term refractive outcome in eyes of preterm infants with and without retinopathy of prematurity: Comparison of keratometric value, axial length, anterior chamber depth, and lens thickness","volume":"84","author":"Choi","year":"2000","journal-title":"Br. J. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/BF02044227","article-title":"Glaucoma as a cause of poor vision in severe retinopathy of prematurity","volume":"231","author":"Hartnett","year":"1993","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1016\/S0161-6420(01)00660-1","article-title":"Adult retinopathy of prematurity: Outcomes of rhegmatogenous retinal detachments and retinal tears","volume":"108","author":"Kaiser","year":"2001","journal-title":"Ophthalmology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1136\/bjo.80.4.343","article-title":"Advanced cicatricial retinopathy of prematurity\u2013outcome and complications","volume":"80","author":"Algawi","year":"1996","journal-title":"Br. J. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1038\/eye.2013.107","article-title":"Adverse events and complications associated with intravitreal injection of anti-VEGF agents: A review of literature","volume":"27","author":"Falavarjani","year":"2013","journal-title":"Eye"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2515","DOI":"10.1056\/NEJMra1208129","article-title":"Mechanisms and management of retinopathy of prematurity","volume":"367","author":"Hartnett","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_10","first-page":"228","article-title":"Treatment of retinopathy of prematurity: A review of conventional and promising new therapeutic options","volume":"6","author":"Mutlu","year":"2013","journal-title":"Int. J. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1136\/bjo.2010.194241","article-title":"Lipid metabolites in the pathogenesis and treatment of neovascular eye disease","volume":"95","author":"Stahl","year":"2011","journal-title":"Br. J. Ophthalmol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1002\/jpen.1497","article-title":"Enteral Docosahexaenoic Acid and Retinopathy of Prematurity: A Randomized Clinical Trial","volume":"43","author":"Calder","year":"2019","journal-title":"J. Parenter. Enter. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1002\/cphy.c120023","article-title":"Bile acid metabolism and signaling","volume":"3","author":"Chiang","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s12177-009-9030-x","article-title":"Bile acids in treatment of ocular disease","volume":"2","author":"Boatright","year":"2009","journal-title":"J. Ocul. Boil. Dis. Informatics"},{"key":"ref_15","first-page":"237","article-title":"UDCA, NorUDCA, and TUDCA in Liver Diseases: A Review of Their Mechanisms of Action and Clinical Applications","volume":"256","author":"Cabrera","year":"2019","journal-title":"Drug Deliv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"58","DOI":"10.7453\/gahmj.2014.017","article-title":"The Unexpected Uses of Urso- and Tauroursodeoxycholic Acid in the Treatment of Non-liver Diseases","volume":"3","author":"Vang","year":"2014","journal-title":"Glob. Adv. Heal. Med."},{"key":"ref_17","first-page":"189","article-title":"Efficacy and safety of tauroursodeoxycholic acid in the treatment of liver cirrhosis: A double-blind randomized controlled trial","volume":"33","author":"Pan","year":"2013","journal-title":"Acta Acad. Med. Wuhan"},{"key":"ref_18","first-page":"610","article-title":"Review: The bile acids urso- and tauroursodeoxycholic acid as neuroprotective therapies in retinal disease","volume":"25","author":"Daruich","year":"2019","journal-title":"Mol. Vis."},{"key":"ref_19","first-page":"101","article-title":"Oxygen-induced retinopathy in the mouse","volume":"35","author":"Smith","year":"1994","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4934","DOI":"10.1167\/iovs.08-2158","article-title":"HMG-CoA reductase inhibitors (statin) prevents retinal neovascularization in a model of oxygen-induced retinopathy","volume":"50","author":"Bartoli","year":"2008","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1096\/fj.02-1084fje","article-title":"VEGF differentially activates STAT3 in microvascular endothelial cells","volume":"17","author":"Bartoli","year":"2003","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"103568","DOI":"10.18632\/oncotarget.21592","article-title":"STAT3-mediated activation of miR-21 is involved in down-regulation of TIMP3 and neovascularization in the ischemic retina","volume":"8","author":"Gutsaeva","year":"2017","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.exer.2011.02.007","article-title":"Trans-Chalcone prevents VEGF expression and retinal neovascularization in the ischemic retina","volume":"93","author":"Lamoke","year":"2011","journal-title":"Exp. Eye Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1007\/s10456-009-9155-3","article-title":"Computer-aided quantification of retinal neovascularization","volume":"12","author":"Stahl","year":"2009","journal-title":"Angiogenesis"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.2337\/db18-0912","article-title":"Monosodium Urate Contributes to Retinal Inflammation and Progression of Diabetic Retinopathy","volume":"68","author":"Thounaojam","year":"2019","journal-title":"Diabetes"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7556","DOI":"10.1167\/iovs.11-7185","article-title":"Differential Expression of Claudins in Retinas during Normal Development and the Angiogenesis of Oxygen-Induced Retinopathy","volume":"52","author":"Luo","year":"2011","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1172\/JCI93825","article-title":"YAP\/TAZ regulates sprouting angiogenesis and vascular barrier maturation","volume":"127","author":"Kim","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13248","DOI":"10.1073\/pnas.1718592114","article-title":"Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy","volume":"114","author":"Thounaojam","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1089\/ars.2016.6638","article-title":"Oral Monomethyl Fumarate Therapy Ameliorates Retinopathy in a Humanized Mouse Model of Sickle Cell Disease","volume":"25","author":"Promsote","year":"2016","journal-title":"Antioxid. Redox Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.1167\/iovs.16-21091","article-title":"TNF?-Induced Disruption of the Blood\u2013Retinal Barrier In Vitro Is Regulated by Intracellular 3?,5?-Cyclic Adenosine Monophosphate Levels","volume":"58","author":"Vogels","year":"2017","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1111\/ceo.12908","article-title":"Lutein facilitates physiological revascularization in a mouse model of retinopathy of prematurity","volume":"45","author":"Fu","year":"2017","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1167\/iovs.09-4098","article-title":"RNA Binding Protein with Multiple Splicing: A New Marker for Retinal Ganglion Cells","volume":"51","author":"Kwong","year":"2010","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/S0002-9440(10)63001-5","article-title":"Inhibition of NAD(P)H Oxidase Activity Blocks Vascular Endothelial Growth Factor Overexpression and Neovascularization during Ischemic Retinopathy","volume":"167","author":"Bartoli","year":"2005","journal-title":"Am. J. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"33189","DOI":"10.1074\/jbc.C000318200","article-title":"Vascular Endothelial Growth Factor Activates STAT Proteins in Aortic Endothelial Cells","volume":"275","author":"Bartoli","year":"2000","journal-title":"J. Boil. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Tsang, J.K.W., Liu, J., and Lo, A.C.Y. (2019). Vascular and Neuronal Protection in the Developing Retina: Potential Therapeutic Targets for Retinopathy of Prematurity. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20174321"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1053\/j.semperi.2019.05.009","article-title":"Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity","volume":"43","author":"Aranda","year":"2019","journal-title":"Semin. Perinatol."},{"key":"ref_37","first-page":"829","article-title":"Analysis on the result of retinopathy of prematurity screening in 1225 premature infants","volume":"48","author":"Jin","year":"2010","journal-title":"Zhonghua Er Ke Za Zhi"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1007\/s12098-017-2404-3","article-title":"An Update on Retinopathy of Prematurity (ROP)","volume":"84","author":"Dogra","year":"2017","journal-title":"Indian J. Pediatr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.2337\/db18-0158","article-title":"Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db\/db Mice","volume":"67","author":"Beli","year":"2018","journal-title":"Diabetes"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.ejphar.2018.09.027","article-title":"Ursodeoxycholic acid ameliorates diabetic retinopathy via reducing retinal inflammation and reversing the breakdown of blood-retinal barrier","volume":"840","author":"Ouyang","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1586\/eop.13.17","article-title":"Targeting Neovascularization in Ischemic Retinopathy: Recent Advances","volume":"8","author":"Elsherbiny","year":"2013","journal-title":"Expert Rev. Ophthalmol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5698","DOI":"10.1167\/iovs.12-10122","article-title":"Aldose Reductase Deficiency Reduced Vascular Changes in Neonatal Mouse Retina in Oxygen-Induced Retinopathy","volume":"53","author":"Fu","year":"2012","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7565","DOI":"10.1167\/iovs.11-8002","article-title":"Reduced retinal neovascularization, vascular permeability, and apoptosis in ischemic retinopathy in the absence of prolyl hydroxylase-1 due to the prevention of hyperoxia-induced vascular obliteration","volume":"52","author":"Huang","year":"2011","journal-title":"Investig. Opthalmol. Vis. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1016\/j.freeradbiomed.2005.06.015","article-title":"Peroxynitrite increases VEGF expression in vascular endothelial cells via STAT3","volume":"39","author":"Platt","year":"2005","journal-title":"Free. Radic. Boil. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.preteyeres.2008.05.001","article-title":"Vascular endothelial growth factor in eye disease","volume":"27","author":"Penn","year":"2008","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Maharjan, P., Kim, D., Jin, M., Ko, H.J., Song, Y.H., Lee, Y., Ahn, B.-N., Shin, M.C., Min, K.A., and Yang, J. (2019). Preclinical Evaluation of UDCA-Containing Oral Formulation in Mice for the Treatment of Wet Age-Related Macular Degeneration. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11110561"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.mam.2017.01.006","article-title":"Bile acids and their receptors","volume":"56","author":"Martinot","year":"2017","journal-title":"Mol. Asp. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1248\/bpb.34.1","article-title":"Effects of chemical modification of ursodeoxycholic acid on TGR5 activation","volume":"34","author":"Iguchi","year":"2011","journal-title":"Boil. Pharm. Bull."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1016\/j.bbalip.2019.07.006","article-title":"Ursodeoxycholic acid is a GPBAR1 agonist and resets liver\/intestinal FXR signaling in a model of diet-induced dysbiosis and NASH","volume":"1864","author":"Carino","year":"2019","journal-title":"Biochim. Biophys. Acta  Mol. Cell Boil. Lipids"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1016\/j.bcp.2005.03.019","article-title":"Regulation of ileal bile acid-binding protein expression in Caco-2 cells by ursodeoxycholic acid: Role of the farnesoid X receptor","volume":"69","author":"Campana","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2231","DOI":"10.1002\/jcp.25742","article-title":"TUDCA: An Agonist of the Bile Acid Receptor GPBAR1\/TGR5 With Anti-Inflammatory Effects in Microglial Cells","volume":"232","year":"2017","journal-title":"J. Cell Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Winston, J.A., Rivera, A., Cai, J., Patterson, A.D., and Theriot, C.M. (2019). Secondary bile acid ursodeoxycholic acid (UDCA) alters weight, the gut microbiota, and the bile acid pool in conventional mice. bioRxiv, 698795.","DOI":"10.1101\/698795"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"451","DOI":"10.3341\/kjo.2018.0011","article-title":"Anti-vascular Endothelial Growth Factor Treatment of Retinopathy of Prematurity: Efficacy, Safety, and Anatomical Outcomes","volume":"32","author":"Kang","year":"2018","journal-title":"Korean J. Ophthalmol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/6\/1921\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:40:52Z","timestamp":1760175652000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/6\/1921"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,19]]},"references-count":53,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["jcm9061921"],"URL":"https:\/\/doi.org\/10.3390\/jcm9061921","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,19]]}}}