{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T08:57:33Z","timestamp":1770281853044,"version":"3.49.0"},"reference-count":32,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T00:00:00Z","timestamp":1633478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010256","name":"Guangzhou Municipal Science and Technology Project","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010256","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014857","name":"National Natural Science Foundation of China-Guangdong Joint Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014857","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016804","name":"Natural Science Foundation of Shenzhen City","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016804","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Objectives:<\/jats:bold> Probenecid is an anion transport inhibitor, which, according to the connectivity map (CMap; a biological application database), interferes with hypoxia-induced gene expression changes in retinal vascular endothelial cells (ECs). Here, we investigated the influence of probenecid on retinal EC cytotoxicity and retinal neovascularization in a murine oxygen-induced retinopathy (OIR) model.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> The retinal EC growth rate in the presence of hypoxia-mimicking concentrations of cobalt chloride (CoCl<jats:sub>2<\/jats:sub>) was determined using the thiazolyl blue tetrazolium bromide (MTT) assay and proliferating cell nuclear antigen (PCNA) expression. In OIR rats, probenecid was administered by intraperitoneal injection (i.p.) from postnatal day (P) 1 to P7. The concentrations of vitreous humor vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1\u03b1, and placental growth factor (PlGF) were determined by using the ELISA kit at P21. The amount of newly formed vascular lumen was evaluated by histopathological examination. Retinopathy and neovascularization were assessed by scoring isolectin B4 fluorescein\u2013stained retinal flat mounts. Western blots for liver tissue HIF-1\u03b1 and hepcidin (HAMP) were performed.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold><jats:italic>In vitro<\/jats:italic>, probenecid led to the recession of the hypoxia-induced EC growth rate. <jats:italic>In vivo<\/jats:italic>, compared to the OIR retina, the upregulation of VEGF, HIF-1\u03b1, and PlGF in phase II retinopathy of prematurity (ROP) was inhibited by probenecid administration. Moreover, probenecid ameliorated neovascularization and resulted in significantly reduced relative leakage fluorescence signal intensity in fluorescein-stained retinal flat mounts (<jats:italic>p<\/jats:italic> &amp;lt; 0.05). Probenecid alleviated the liver overactivation of HAMP and downregulation of HIF-1\u03b1 in OIR rats.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> This is the first demonstration that implies that probenecid might be a protective compound against retinal angiogenesis in OIR. These changes are accompanied with decreased hyperoxia-mediated hepcidin overproduction. Although the relevance of the results to ROP needs further research, these findings may help establish potential pharmacological targets based on the CMap database.<\/jats:p>","DOI":"10.3389\/fphar.2021.717351","type":"journal-article","created":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T10:07:51Z","timestamp":1633601271000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Effect of Probenecid on Endothelial Cell Growth Rate and Retinal Angiogenesis in an Oxygen-Induced Retinopathy Model"],"prefix":"10.3389","volume":"12","author":[{"given":"Jingbo","family":"Jiang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiming","family":"Ou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianqiong","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianwen","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guosheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuiqing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongping","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Longkai","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiamin","family":"Gan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shasha","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuan","family":"Nie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"CD004868","DOI":"10.1002\/14651858.CD004868.pub5","article-title":"Late erythropoiesis-stimulating agents to prevent red blood cell transfusion in preterm or low birth weight infants","volume":"2","author":"Aher","year":"2019","journal-title":"Cochrane Database Syst. 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