{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T03:39:49Z","timestamp":1784086789597,"version":"3.55.0"},"reference-count":46,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100031495","name":"YOKOYAMA Foundation for Clinical Pharmacology","doi-asserted-by":"crossref","award":["#YRY-2105"],"award-info":[{"award-number":["#YRY-2105"]}],"id":[{"id":"10.13039\/100031495","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Eye Research Foundation for the Aged"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Retinal vein occlusion (RVO) is a common vascular disease that leads to vision loss due to macular edema (ME). This study investigated the role of autotaxin (ATX), a lysophospholipase D, in the pathogenesis of RVO. In mice, RVO was induced by intravenous administration of rose bengal followed by laser irradiation of retinal veins. ATX expression in the retina was evaluated using immunohistochemistry. Intravitreal ATX was administered, and retinal changes were assessed using fluorescence angiography and optical coherence tomography (OCT). In human retinal microvascular endothelial cells (HRMECs), intercellular barrier function was evaluated using transepithelial electrical resistance (TEER). In the murine RVO model, the ATX inhibitor HA130 was administered intravitreally, and retinal thickness was measured and compared using OCT. ATX expression was increased in retinal vessels in the RVO model. Intravitreal administration of ATX induced retinal edema and serous retinal detachment (SRD). ATX significantly disrupted the barrier integrity of HRMECs and promoted the expression of vascular endothelial growth factor (VEGF), which was ameliorated by HA130. Intravitreal administration of HA130 significantly reduced retinal thickening caused by retinal edema secondary to RVO and the elevated expression of intercellular adhesion molecule (ICAM)-1 in the retina. These findings suggest that ATX plays a critical role in RVO-induced ME by disrupting endothelial barrier integrity, potentially through the upregulation of VEGF in retinal endothelial cells and subsequent ICAM-1 upregulation in the retina.<\/jats:p>","DOI":"10.3390\/ijms27062776","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T08:54:37Z","timestamp":1773910477000},"page":"2776","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Role of Autotaxin in the Pathogenesis of Retina Ischemia and Its Therapeutic Implications"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6182-4343","authenticated-orcid":false,"given":"Ryo","family":"Terao","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryosuke","family":"Fujino","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8626-0572","authenticated-orcid":false,"given":"Kentaro","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7385-415X","authenticated-orcid":false,"given":"Takafumi","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0598-3248","authenticated-orcid":false,"given":"Shota","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2754-3593","authenticated-orcid":false,"given":"Reiko","family":"Yamagishi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Ueta","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyasu","family":"Shiraya","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"},{"name":"Department of Ophthalmology, Showa General Hospital, Tokyo 187-8510, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumi","family":"Honjo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Aihara","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1097\/IAE.0000000000000843","article-title":"Retinal Vein Occlusions, from Basics to the Latest Treatment","volume":"36","author":"Ho","year":"2016","journal-title":"Retina"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1097\/IAE.0b013e3182870c15","article-title":"Branch retinal vein occlusion: Epidemiology, pathogenesis, risk factors, clinical features, diagnosis, and complications. An update of the literature","volume":"33","author":"Jaulim","year":"2013","journal-title":"Retina"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ajo.2008.07.024","article-title":"Etiology and treatment of macular edema","volume":"147","author":"Johnson","year":"2009","journal-title":"Am. J. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1080\/02713680701851902","article-title":"Branch retinal vein occlusion: Pathogenesis, visual prognosis, and treatment modalities","volume":"33","author":"Rehak","year":"2008","journal-title":"Curr. Eye Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wang, B., Zhang, X., Chen, H., Koh, A., Zhao, C., and Chen, Y. (2022). A Review of Intraocular Biomolecules in Retinal Vein Occlusion: Toward Potential Biomarkers for Companion Diagnostics. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.859951"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.12688\/f1000research.19198.1","article-title":"Emerging therapies in the management of macular edema: A review","volume":"8","author":"Sacconi","year":"2019","journal-title":"F1000Research"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"S10","DOI":"10.5301\/EJO.2010.6050","article-title":"General pathophysiology of macular edema","volume":"21","author":"Scholl","year":"2011","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.5301\/EJO.2010.6049","article-title":"Blood-retinal barrier","volume":"21","author":"Bernardes","year":"2011","journal-title":"Eur. J. Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1953","DOI":"10.2337\/diabetes.47.12.1953","article-title":"Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: Vascular endothelial growth factor decreases occludin in retinal endothelial cells. Penn State Retina Research Group","volume":"47","author":"Antonetti","year":"1998","journal-title":"Diabetes"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105115","DOI":"10.1016\/j.phrs.2020.105115","article-title":"Regulation of blood-retinal barrier cell-junctions in diabetic retinopathy","volume":"161","author":"Rudraraju","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.jfo.2014.10.003","article-title":"Management of macular edema secondary to retinal vein occlusion","volume":"38","author":"Girmens","year":"2015","journal-title":"J. Fr. Ophtalmol."},{"key":"ref_12","first-page":"546","article-title":"Update on the Use of Anti-VEGF Intravitreal Therapies for Retinal Vein Occlusions","volume":"6","author":"Jiang","year":"2017","journal-title":"Asia Pac. J. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"328","DOI":"10.2174\/1573399811666150615151324","article-title":"Anti-VEGF Therapy for Retinal Vein Occlusions","volume":"17","author":"Campa","year":"2016","journal-title":"Curr. Drug Targets"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1517\/14712598.2015.1086744","article-title":"Intravitreal steroid and anti-vascular endothelial growth agents for the management of retinal vein occlusion: Evidence from randomized trials","volume":"15","author":"Chatziralli","year":"2015","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e000249","DOI":"10.1136\/bmjophth-2018-000249","article-title":"Five-year outcomes of retinal vein occlusion treated with vascular endothelial growth factor inhibitors","volume":"4","author":"Spooner","year":"2019","journal-title":"BMJ Open Ophthalmol."},{"key":"ref_16","first-page":"601","article-title":"Function and biological activities of the autotaxin-LPA axis","volume":"63","author":"Li","year":"2011","journal-title":"Sheng Li Xue Bao"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Terao, R., and Kaneko, H. (2020). Lipid Signaling in Ocular Neovascularization. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134758"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejphar.2015.08.028","article-title":"The autotaxin-lysophosphatidic acid pathway in pathogenesis of rheumatoid arthritis","volume":"765","author":"Orosa","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1167\/iovs.17-22807","article-title":"Role of the Autotaxin-LPA Pathway in Dexamethasone-Induced Fibrotic Responses and Extracellular Matrix Production in Human Trabecular Meshwork Cells","volume":"59","author":"Honjo","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1167\/iovs.17-23218","article-title":"Autotaxin-Lysophosphatidic Acid Pathway in Intraocular Pressure Regulation and Glaucoma Subtypes","volume":"59","author":"Honjo","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Iyer, P., Lalane, R., Morris, C., Challa, P., Vann, R., and Rao, P.V. (2012). Autotaxin-lysophosphatidic acid axis is a novel molecular target for lowering intraocular pressure. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042627"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1097\/IAE.0000000000001112","article-title":"Lysophosphatidic Acids and Autotaxin in Retinal Vein Occlusion","volume":"36","author":"Dacheva","year":"2016","journal-title":"Retina"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"108441","DOI":"10.1016\/j.exer.2021.108441","article-title":"Establishment of a pigmented murine model abundant with characteristics of retinal vein occlusion","volume":"204","author":"Miyagi","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Meaux, M.N., Regnier, M., Portefaix, A., Borel, O., Alioli, C., Peyruchaud, O., Legrand, M., and Bacchetta, J. (2023). Circulating autotaxin levels in healthy teenagers: Data from the Vitados cohort. Front. Pediatr., 11.","DOI":"10.3389\/fped.2023.1094705"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1002\/(SICI)1097-4695(199912)41:4<495::AID-NEU5>3.0.CO;2-K","article-title":"Lysophosphatidic acid-induced Ca2+ mobilization in the neural retina of chick embryo","volume":"41","author":"Zhou","year":"1999","journal-title":"J. Neurobiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1159\/000364858","article-title":"G-protein-coupled receptor cell signaling pathways mediating embryonic chick retinal growth cone collapse induced by lysophosphatidic acid and sphingosine-1-phosphate","volume":"36","author":"Fincher","year":"2014","journal-title":"Dev. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"Uhlen","year":"2015","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.1093\/hmg\/ddq129","article-title":"Transcriptome analysis and molecular signature of human retinal pigment epithelium","volume":"19","author":"Strunnikova","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.bbalip.2018.04.007","article-title":"Role of lysophosphatidic acid in the retinal pigment epithelium and photoreceptors","volume":"1863","author":"Lidgerwood","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Cell Biol. Lipids"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/ni1573","article-title":"Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs","volume":"9","author":"Kanda","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Bhattarai, S., Subedi, U., Manikandan, S., Sharma, S., Sharma, P., Miller, C., Bhuiyan, M.S., Kidambi, S., Aidinis, V., and Sun, H. (2023). Endothelial Specific Deletion of Autotaxin Improves Stroke Outcomes. Cells, 12.","DOI":"10.3390\/cells12030511"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Qu, M., Long, Y., Wang, Y., Yin, N., Zhang, X., and Zhang, J. (2023). Hypoxia Increases ATX Expression by Histone Crotonylation in a HIF-2alpha-Dependent Manner. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24087031"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Zhang, X., Li, M., Yin, N., and Zhang, J. (2021). The Expression Regulation and Biological Function of Autotaxin. Cells, 10.","DOI":"10.3390\/cells10040939"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1097\/00004397-200404440-00006","article-title":"Diabetic macular edema: A review of past, present, and future therapies","volume":"44","author":"Thompson","year":"2004","journal-title":"Int. Ophthalmol. Clin."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"189","DOI":"10.18231\/j.ijceo.2020.041","article-title":"A study of ocular morbidities associated with retinal vein occlusion","volume":"6","author":"Khandelwal","year":"2020","journal-title":"Indian J. Clin. Exp. Ophthalmol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1158\/1541-7786.MCR-09-0288","article-title":"Autotaxin signaling via lysophosphatidic acid receptors contributes to vascular endothelial growth factor-induced endothelial cell migration","volume":"8","author":"Ptaszynska","year":"2010","journal-title":"Mol. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bhattarai, S., Sharma, S., Subedi, U., Ara, H., Shum, A., Milena, M., Bhuiyan, M.S., Kidambi, S., Sun, H., and Miriyala, S. (2022). The ATX-LPA Axis Regulates Vascular Permeability during Cerebral Ischemic-Reperfusion. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084138"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"399","DOI":"10.3233\/CH-190732","article-title":"Autotaxin inhibition attenuates endothelial permeability after ischemia-reperfusion injury","volume":"75","author":"Strumwasser","year":"2020","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1158\/1541-7786.MCR-07-0143","article-title":"Positive feedback between vascular endothelial growth factor-A and autotaxin in ovarian cancer cells","volume":"6","author":"Ptaszynska","year":"2008","journal-title":"Mol. Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1159\/000494177","article-title":"High Glucose Induces VEGF-C Expression via the LPA1\/3-Akt-ROS-LEDGF Signaling Axis in Human Prostate Cancer PC-3 Cells","volume":"50","author":"Huang","year":"2018","journal-title":"Cell Physiol. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6467","DOI":"10.18632\/aging.204249","article-title":"Effect of BBT-877, a novel inhibitor of ATX, on a mouse model of type 1 diabetic nephropathy","volume":"14","author":"Lee","year":"2022","journal-title":"Aging"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jphs.2018.06.010","article-title":"Effects of ripasudil, a ROCK inhibitor, on retinal edema and nonperfusion area in a retinal vein occlusion murine model","volume":"137","author":"Hida","year":"2018","journal-title":"J. Pharmacol. Sci."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"She, S., Zhang, Q., Shi, J., Yang, F., and Dai, K. (2022). Roles of Autotaxin\/Autotaxin-Lysophosphatidic Acid Axis in the Initiation and Progression of Liver Cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.922945"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1186\/s12974-020-01809-1","article-title":"MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia","volume":"17","author":"Plastira","year":"2020","journal-title":"J. Neuroinflammation"},{"key":"ref_45","first-page":"1383","article-title":"Identification of primary retinal cells and ex vivo detection of proinflammatory molecules using flow cytometry","volume":"15","author":"Portillo","year":"2009","journal-title":"Mol. Vis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.12688\/f1000research.15409.1","article-title":"A convenient protocol for establishing a human cell culture model of the outer retina","volume":"7","author":"Lynn","year":"2018","journal-title":"F1000Research"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2776\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T05:18:49Z","timestamp":1774070329000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2776"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,19]]},"references-count":46,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062776"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062776","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,19]]}}}