{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T16:46:42Z","timestamp":1776703602718,"version":"3.51.2"},"reference-count":56,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T00:00:00Z","timestamp":1595980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Retinal ischemia contributes to visual impairment in ischemic retinopathies. A disintegrin and metalloproteinase ADAM17 is implicated in multiple vascular pathologies through its ability to regulate inflammatory signaling via ectodomain shedding. We investigated the role of endothelial ADAM17 in neuronal and vascular degeneration associated with retinal ischemia reperfusion (IR) injury using mice with conditional inactivation of ADAM17 in vascular endothelium. ADAM17Cre-flox and control ADAM17flox mice were subjected to 40 min of pressure-induced retinal ischemia, with the contralateral eye serving as control. Albumin extravasation and retinal leukostasis were evaluated 48 h after reperfusion. Retinal morphometric analysis was conducted 7 days after reperfusion. Degenerate capillaries were assessed by elastase digest and visual function was evaluated by optokinetic test 14 and 7 days following ischemia, respectively. Lack of ADAM17 decreased vascular leakage and reduced retinal thinning and ganglion cell loss in ADAM17Cre-flox mice. Further, ADAM17Cre-flox mice exhibited a remarkable reduction in capillary degeneration following IR. Decrease in neurovascular degeneration in ADAM17Cre-flox mice correlated with decreased activation of caspase-3 and was associated with reduction in oxidative stress and retinal leukostasis. In addition, knockdown of ADAM17 resulted in decreased cleavage of p75NTR, the process known to be associated with retinal cell apoptosis. A decline in visual acuity evidenced by decrease in spatial frequency threshold observed in ADAM17flox mice was partially restored in ADAM17-endothelial deficient mice. The obtained results provide evidence that endothelial ADAM17 is an important contributor to IR-induced neurovascular damage in the retina and suggest that interventions directed at regulating ADAM17 activity can be beneficial for alleviating the consequences of retinal ischemia.<\/jats:p>","DOI":"10.3390\/ijms21155379","type":"journal-article","created":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T07:31:45Z","timestamp":1596007905000},"page":"5379","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Inactivation of Endothelial ADAM17 Reduces Retinal Ischemia-Reperfusion Induced Neuronal and Vascular Damage"],"prefix":"10.3390","volume":"21","author":[{"given":"Diana R","family":"Gutsaeva","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lamiaa","family":"Shalaby","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Folami L","family":"Powell","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Menaka C","family":"Thounaojam","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hossameldin","family":"Abouhish","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"},{"name":"Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, 35516 Mansoura, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara A","family":"Wetzstein","sequence":"additional","affiliation":[{"name":"School of Medicine, Mercer University, Macon, GA 31207, 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, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6349-4517","authenticated-orcid":false,"given":"Hang Fai","family":"Kwok","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Macau 999078"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pamela M","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical College of Georgia, 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":[[2020,7,29]]},"reference":[{"key":"ref_1","first-page":"694","article-title":"Patterns of ischemia in diabetic retinopathy","volume":"81","author":"Bresnick","year":"1976","journal-title":"Trans. Sect. Ophthalmol. Am. Acad. Ophthalmol. Otolaryngol."},{"key":"ref_2","first-page":"59","article-title":"Molecular mechanisms of retinal ischemia","volume":"126","author":"Neroev","year":"2010","journal-title":"Vestn. Oftalmol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.preteyeres.2003.12.001","article-title":"Retinal ischemia: Mechanisms of damage and potential therapeutic strategies","volume":"23","author":"Osborne","year":"2004","journal-title":"Prog. Retin Eye Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/B978-0-12-394309-5.00006-7","article-title":"Cell biology of ischemia\/reperfusion injury","volume":"298","author":"Kalogeris","year":"2012","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_5","first-page":"367","article-title":"Low-dose minocycline mediated neuroprotection on retinal ischemia-reperfusion injury of mice","volume":"24","author":"Huang","year":"2018","journal-title":"Mol. Vis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1167\/iovs.07-1050","article-title":"Quantification of ischemic damage in the rat retina: A comparative study using evoked potentials, electroretinography, and histology","volume":"49","author":"Jehle","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"174","DOI":"10.3389\/fncel.2019.00174","article-title":"From Ganglion Cell to Photoreceptor Layer: Timeline of Deterioration in a Rat Ischemia\/Reperfusion Model","volume":"13","author":"Palmhof","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1038\/s41419-018-1051-6","article-title":"Arginase 1 promotes retinal neurovascular protection from ischemia through suppression of macrophage inflammatory responses","volume":"9","author":"Fouda","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1167\/iovs.06-0510","article-title":"Retinal ischemia and reperfusion causes capillary degeneration: Similarities to diabetes","volume":"48","author":"Zheng","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5920","DOI":"10.1167\/iovs.10-5264","article-title":"Effects of ischemic preconditioning and bevacizumab on apoptosis and vascular permeability following retinal ischemia-reperfusion injury","volume":"51","author":"Abcouwer","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Liu, L., Jiang, Y., and Steinle, J.J. (2018). Epac1 protects the retina against ischemia\/reperfusion-induced neuronal and vascular damage. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0204346"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1016\/j.ajpath.2018.06.020","article-title":"Inhibition of Atypical Protein Kinase C Reduces Inflammation-Induced Retinal Vascular Permeability","volume":"188","author":"Lin","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.freeradbiomed.2011.04.026","article-title":"Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia-reperfusion injury","volume":"51","author":"Wei","year":"2011","journal-title":"Free Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S0002-9440(10)63952-1","article-title":"Leukocyte-mediated endothelial cell injury and death in the diabetic retina","volume":"158","author":"Joussen","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/385729a0","article-title":"A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells","volume":"385","author":"Black","year":"1997","journal-title":"Nature"},{"key":"ref_16","first-page":"1756","article-title":"Tumor necrosis factor-alpha (TNF-alpha) converting enzyme contributes to production of TNF-alpha in synovial tissues from patients with rheumatoid arthritis","volume":"28","author":"Ohta","year":"2001","journal-title":"J. Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1124\/jpet.103.059675","article-title":"Identification and characterization of 4-[[4-(2-butynyloxy)phenyl]sulfonyl]-N-hydroxy-2,2-dimethyl-(3S)thiomorpholinecar boxamide (TMI-1), a novel dual tumor necrosis factor-alpha-converting enzyme\/matrix metalloprotease inhibitor for the treatment of rheumatoid arthritis","volume":"309","author":"Zhang","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_18","first-page":"598","article-title":"BMS-561392. Bristol-Myers Squibb","volume":"4","author":"Grootveld","year":"2003","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1002\/emmm.201200217","article-title":"Lung endothelial ADAM17 regulates the acute inflammatory response to lipopolysaccharide","volume":"4","author":"Dreymueller","year":"2012","journal-title":"EMBO Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2335","DOI":"10.1158\/1078-0432.CCR-06-2092","article-title":"ADAM-17 expression in breast cancer correlates with variables of tumor progression","volume":"13","author":"McGowan","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.2174\/0929867023370121","article-title":"The search for alpha-secretase and its potential as a therapeutic approach to Alzheimer s disease","volume":"9","author":"Hooper","year":"2002","journal-title":"Curr. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/ncprheum0797","article-title":"Drug insight: Tumor necrosis factor-converting enzyme as a pharmaceutical target for rheumatoid arthritis","volume":"4","author":"Moss","year":"2008","journal-title":"Nat. Clin. Pract. Rheumatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.atherosclerosis.2005.08.031","article-title":"The TNF alpha converting enzyme (TACE\/ADAM17) is expressed in the atherosclerotic lesions of apolipoprotein E-deficient mice: Possible contribution to elevated plasma levels of soluble TNF alpha receptors","volume":"187","author":"Canault","year":"2006","journal-title":"Atherosclerosis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/385733a0","article-title":"Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha","volume":"385","author":"Moss","year":"1997","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"37459","DOI":"10.1074\/jbc.M305877200","article-title":"Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-alpha-converting enzyme (ADAM 17)","volume":"278","author":"Garton","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1002\/eji.200535257","article-title":"ADAM17 activity during human neutrophil activation and apoptosis","volume":"36","author":"Walcheck","year":"2006","journal-title":"Eur. J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6362","DOI":"10.4049\/jimmunol.172.10.6362","article-title":"The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10","volume":"172","author":"Abel","year":"2004","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4799","DOI":"10.1182\/blood-2008-04-152330","article-title":"Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases","volume":"113","author":"Koenen","year":"2009","journal-title":"Blood"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1126\/science.282.5392.1281","article-title":"An essential role for ectodomain shedding in mammalian development","volume":"282","author":"Peschon","year":"1998","journal-title":"Science"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1161\/HYPERTENSIONAHA.110.166892","article-title":"A disintegrin and metalloprotease 17 mediates neointimal hyperplasia in vasculature","volume":"57","author":"Takaguri","year":"2011","journal-title":"Hypertension"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1161\/HYPERTENSIONAHA.117.09822","article-title":"Vascular ADAM17 (a Disintegrin and Metalloproteinase Domain 17) Is Required for Angiotensin II\/beta-Aminopropionitrile-Induced Abdominal Aortic Aneurysm","volume":"70","author":"Kawai","year":"2017","journal-title":"Hypertension"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1161\/ATVBAHA.117.309430","article-title":"Role of Adipose Tissue Endothelial ADAM17 in Age-Related Coronary Microvascular Dysfunction","volume":"37","author":"Dou","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1161\/HYPERTENSIONAHA.116.07620","article-title":"Vascular ADAM17 as a Novel Therapeutic Target in Mediating Cardiovascular Hypertrophy and Perivascular Fibrosis Induced by Angiotensin II","volume":"68","author":"Takayanagi","year":"2016","journal-title":"Hypertension"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1161\/CIRCRESAHA.109.207415","article-title":"Pathological neovascularization is reduced by inactivation of ADAM17 in endothelial cells but not in pericytes","volume":"106","author":"Weskamp","year":"2010","journal-title":"Circ. Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Shalaby, L., Thounaojam, M., Tawfik, A., Li, J., Hussein, K., Jahng, W.J., Al-Shabrawey, M., Kwok, H.F., Bartoli, M., and Gutsaeva, D. (2020). Role of Endothelial ADAM17 in Early Vascular Changes Associated with Diabetic Retinopathy. J. Clin. Med., 9.","DOI":"10.3390\/jcm9020400"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1017\/S0952523805225166","article-title":"Independent visual threshold measurements in the two eyes of freely moving rats and mice using a virtual-reality optokinetic system","volume":"22","author":"Douglas","year":"2005","journal-title":"Vis. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2883","DOI":"10.1172\/JCI118746","article-title":"Accelerated death of retinal microvascular cells in human and experimental diabetic retinopathy","volume":"97","author":"Mizutani","year":"1996","journal-title":"J. Clin. Investig."},{"key":"ref_38","first-page":"1471","article-title":"Ischemia and reperfusion-induced histologic changes in the rat retina. Demonstration of a free radical-mediated mechanism","volume":"32","author":"Szabo","year":"1991","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1186\/1742-2094-10-149","article-title":"Minocycline prevents retinal inflammation and vascular permeability following ischemia-reperfusion injury","volume":"10","author":"Abcouwer","year":"2013","journal-title":"J. Neuroinflamm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4241","DOI":"10.1074\/jbc.M307974200","article-title":"Evidence for a critical role of the tumor necrosis factor alpha convertase (TACE) in ectodomain shedding of the p75 neurotrophin receptor (p75NTR)","volume":"279","author":"Weskamp","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"20358","DOI":"10.1074\/jbc.M109.082834","article-title":"p75 neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-alpha-converting enzyme\/ADAM17","volume":"285","author":"Kenchappa","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_42","first-page":"205","article-title":"Farnsworth-Munsell 100-hue test for patients with diabetes mellitus","volume":"24","author":"Utku","year":"1992","journal-title":"Ann. Ophthalmol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.optom.2013.03.003","article-title":"Visual functions and disability in diabetic retinopathy patients","volume":"7","author":"Shrestha","year":"2014","journal-title":"J. Optom."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2904","DOI":"10.1167\/iovs.13-11659","article-title":"Diabetes-induced impairment in visual function in mice: Contributions of p38 MAPK, rage, leukocytes, and aldose reductase","volume":"55","author":"Lee","year":"2014","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8123","DOI":"10.1167\/iovs.11-8318","article-title":"Neuroprotection from retinal ischemia\/reperfusion injury by NOX2 NADPH oxidase deletion","volume":"52","author":"Yokota","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3157","DOI":"10.1074\/jbc.M510797200","article-title":"Tumor necrosis factor-alpha-converting enzyme (TACE\/ADAM-17) mediates the ectodomain cleavage of intercellular adhesion molecule-1 (ICAM-1)","volume":"281","author":"Tsakadze","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1172\/JCI656","article-title":"Leukocyte-endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF-kB-dependent fashion","volume":"101","author":"Morigi","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1016\/S1567-5769(02)00058-9","article-title":"The role of NF-kappaB in the regulation of cell stress responses","volume":"2","author":"Wang","year":"2002","journal-title":"Int. Immunopharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"15013","DOI":"10.1038\/mtm.2015.13","article-title":"Silencing p75(NTR) prevents proNGF-induced endothelial cell death and development of acellular capillaries in rat retina","volume":"2","author":"Shanab","year":"2015","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.mcn.2007.08.005","article-title":"Photic injury promotes cleavage of p75NTR by TACE and nuclear trafficking of the p75 intracellular domain","volume":"36","author":"Srinivasan","year":"2007","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Kuo, M.H., Lee, H.F., Tu, Y.F., Lin, L.H., Cheng, Y.Y., and Lee, H.T. (2019). Astaxanthin Ameliorates Ischemic-Hypoxic-Induced Neurotrophin Receptor p75 Upregulation in the Endothelial Cells of Neonatal Mouse Brains. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20246168"},{"key":"ref_52","first-page":"129","article-title":"Deletion of the Neurotrophin Receptor p75(NTR) Prevents Diabetes-Induced Retinal Acellular Capillaries in Streptozotocin-Induced Mouse Diabetic Model","volume":"4","author":"Mohamed","year":"2017","journal-title":"J. Diabetes Metab. Disord. Control"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1002\/dvdy.20643","article-title":"VE-Cadherin-Cre-recombinase transgenic mouse: A tool for lineage analysis and gene deletion in endothelial cells","volume":"235","author":"Alva","year":"2006","journal-title":"Dev. Dyn."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/9780470942390.mo140190","article-title":"Diabetic Retinopathy: Retina-Specific Methods for Maintenance of Diabetic Rodents and Evaluation of Vascular Histopathology and Molecular Abnormalities","volume":"5","author":"Veenstra","year":"2015","journal-title":"Curr. Protoc. Mouse Biol."},{"key":"ref_55","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_56","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1167\/iovs.18-26433","article-title":"Transducin1, Phototransduction and the Development of Early Diabetic Retinopathy","volume":"60","author":"Liu","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/15\/5379\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:52:31Z","timestamp":1760176351000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/15\/5379"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,29]]},"references-count":56,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["ijms21155379"],"URL":"https:\/\/doi.org\/10.3390\/ijms21155379","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,29]]}}}