{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:24:26Z","timestamp":1787117066484,"version":"build-2736575974"},"reference-count":32,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2025-24803067"],"award-info":[{"award-number":["RS-2025-24803067"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2025-24803067"],"award-info":[{"award-number":["RS-2025-24803067"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Catholic Medical Center Research Foundation","award":["program year of 2026"],"award-info":[{"award-number":["program year of 2026"]}]},{"award":["program year of 2026"],"award-info":[{"award-number":["program year of 2026"]}],"id":[{"id":"https:\/\/ror.org\/00ng7yn96","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Chronic hyperglycemia disrupts the retinal neurovascular unit, making diabetic retinopathy (DR) the leading cause of adult vision loss. The hallmarks of DR include pathological angiogenesis, vascular leakage, and neurodegeneration. Although vascular endothelial growth factor A (VEGF-A) is a key mediator of these abnormalities and anti-VEGF therapies remain the standard treatment, many patients exhibit incomplete responses, and these therapies do not adequately address inflammation or fibrosis. Placental growth factor (PlGF), a VEGF family member that selectively binds to VEGFR1, has emerged as an important contributor to retinal neovascularization, vascular dysfunction, barrier breakdown, and microinflammation in DR. Unlike VEGF-A, PlGF modulates distinct responses among retinal neurons, glial cells, and vascular cells, with its abnormal expression closely associated with disease progression from non-proliferative to proliferative DR. This review summarizes the context-dependent functions of PlGF in the diabetic retina, compares PlGF\u2013VEGFR1 signaling with VEGF-A\u2013VEGFR2 pathways, and discusses preclinical and clinical evidence supporting PlGF inhibition as a potential complementary approach to existing anti-VEGF therapy.<\/jats:p>","DOI":"10.3390\/ijms27167354","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T16:35:08Z","timestamp":1786984508000},"page":"7354","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Placental Growth Factor in Diabetic Retinopathy: Disease-Selective Signaling and Mechanistic Rationale for Targeted Therapy"],"prefix":"10.3390","volume":"27","author":[{"given":"Jongmin","family":"Kim","sequence":"first","affiliation":[{"name":"POSTECH-Catholic Biomedical Engineering Institute, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1117-4834","authenticated-orcid":false,"given":"Won-Kyu","family":"Ju","sequence":"additional","affiliation":[{"name":"Viterbi Family Department of Ophthalmology, Viterbi Family Vision Research Center, Shiley Eye Institute, University of California San Diego, La Jolla, CA 92039, USA"},{"name":"Institute of Engineering in Medicine, Shu Chien\u2014Gene Lay Department of Bioengineering, University of California San Diego, La Jolla, CA 92039, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8694-9043","authenticated-orcid":false,"given":"Jae Yon","family":"Won","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Science, Eunpyeong St. Mary\u2019s Hospital, The Catholic University of Korea, Seoul 03312, Republic of Korea"},{"name":"Catholic Institute for Visual Science, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1056\/NEJM199412013312203","article-title":"Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders","volume":"331","author":"Aiello","year":"1994","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Wang, W., and Lo, A.C. (2018). Diabetic retinopathy: Pathophysiology and treatments. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061816"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.preteyeres.2018.10.006","article-title":"The role of placental growth factor (PlGF) and its receptor system in retinal vascular diseases","volume":"69","author":"Etienne","year":"2019","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.exer.2017.09.012","article-title":"Neutralization of placental growth factor as a novel treatment option in diabetic retinopathy","volume":"165","author":"Hu","year":"2017","journal-title":"Exp. Eye Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0002-9394(01)01269-7","article-title":"Increased levels of vascular endothelial growth factor and interleukin-6 in the aqueous humor of diabetics with macular edema","volume":"133","author":"Funatsu","year":"2002","journal-title":"Am. J. Ophthalmol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1167\/iovs.02-0807","article-title":"VEGF164 is proinflammatory in the diabetic retina","volume":"44","author":"Ishida","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/eye.2016.246","article-title":"Vitreous levels of placental growth factor correlate with activity of proliferative diabetic retinopathy and are not influenced by bevacizumab treatment","volume":"31","author":"Xu","year":"2017","journal-title":"Eye"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1111\/aos.13325","article-title":"Placental growth factor and its potential role in diabetic retinopathy and other ocular neovascular diseases","volume":"96","author":"Nguyen","year":"2018","journal-title":"Acta Ophthalmol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13695","DOI":"10.1096\/fj.201901353R","article-title":"Placental growth factor negatively regulates retinal endothelial cell barrier function through suppression of glucose-6-phosphate dehydrogenase and antioxidant defense systems","volume":"33","author":"Huang","year":"2019","journal-title":"FASEB J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"15339","DOI":"10.1038\/s41598-019-51603-0","article-title":"Distinct downstream signaling and the roles of VEGF and PlGF in high glucose-mediated injuries of human retinal endothelial cells in culture","volume":"9","author":"Jiao","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"103682","DOI":"10.1016\/j.jprot.2020.103682","article-title":"Placental growth factor regulates the pentose phosphate pathway and antioxidant defense systems in human retinal endothelial cells","volume":"217","author":"Saddala","year":"2020","journal-title":"J. Proteom."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"100954","DOI":"10.1016\/j.preteyeres.2021.100954","article-title":"VEGFR1 signaling in retinal angiogenesis and microinflammation","volume":"84","author":"Uemura","year":"2021","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Huang, H. (2020). Pericyte-endothelial interactions in the retinal microvasculature. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197413"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kowalczuk, L., Touchard, E., Omri, S., Jonet, L., Klein, C., Valamanes, F., Berdugo, M., Bigey, P., Massin, P., and Jeanny, J.-C. (2011). Placental growth factor contributes to micro-vascular abnormalization and blood-retinal barrier breakdown in diabetic retinopathy. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017462"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.bcp.2019.07.021","article-title":"Aflibercept regulates retinal inflammation elicited by high glucose via the PlGF\/ERK pathway","volume":"168","author":"Lazzara","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lazzara, F., Trotta, M.C., Platania, C.B.M., D\u2019Amico, M., Petrillo, F., Galdiero, M., Gesualdo, C., Rossi, S., Drago, F., and Bucolo, C. (2020). Stabilization of HIF-1\u03b1 in human retinal endothelial cells modulates expression of miRNAs and proangiogenic growth factors. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.01063"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.exer.2013.07.018","article-title":"VEGF but not PlGF disturbs the barrier of retinal endothelial cells","volume":"115","author":"Deissler","year":"2013","journal-title":"Exp. Eye Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/87904","article-title":"Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions","volume":"7","author":"Carmeliet","year":"2001","journal-title":"Nat. Med."},{"key":"ref_19","first-page":"5179","article-title":"Comparison of serum and vitreous PIGF in diabetic retinopathy patients and non-diabetic patients","volume":"56","author":"Mesquita","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e482","DOI":"10.1111\/aos.13426","article-title":"Aqueous humour concentrations of TGF-\u03b2, PLGF and FGF-1 and total retinal blood flow in patients with early non-proliferative diabetic retinopathy","volume":"97","author":"Du","year":"2019","journal-title":"Acta Ophthalmol."},{"key":"ref_21","first-page":"e54862","article-title":"Serum and vitreous levels of Placenta Growth factor in Diabetic Retinopathy patients: Correlation with Disease Severity and Optical Coherence Tomographic parameters","volume":"16","author":"Mesquita","year":"2024","journal-title":"Cureus"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1007\/s00417-021-05515-3","article-title":"Comparison of before versus after intravitreal bevacizumab injection, growth factor levels and fibrotic markers in vitreous samples from patients with proliferative diabetic retinopathy","volume":"260","author":"Ozer","year":"2022","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"200","DOI":"10.2337\/db14-0016","article-title":"Deletion of placental growth factor prevents diabetic retinopathy and is associated with Akt activation and HIF1\u03b1-VEGF pathway inhibition","volume":"64","author":"Huang","year":"2015","journal-title":"Diabetes"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"101799","DOI":"10.1016\/j.redox.2020.101799","article-title":"Oxidative stress and diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications","volume":"37","author":"Kang","year":"2020","journal-title":"Redox Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"16728","DOI":"10.1038\/s41598-018-34955-x","article-title":"Proteomics reveals ablation of PlGF increases antioxidant and neuroprotective proteins in the diabetic mouse retina","volume":"8","author":"Saddala","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e008405","DOI":"10.1136\/bmjopen-2015-008405","article-title":"Clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (acronym CLARITY): A multicentre phase IIb randomised active-controlled clinical trial","volume":"5","author":"Sivaprasad","year":"2015","journal-title":"BMJ Open"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.2147\/OPTH.S316271","article-title":"Aflibercept versus ranibizumab as a second line therapy after bevacizumab for diabetic macular edema","volume":"15","author":"Alsaedi","year":"2021","journal-title":"Clin. Ophthalmol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S2213-8587(16)30052-3","article-title":"Diabetic macular oedema","volume":"5","author":"Tan","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/nm884","article-title":"Role of PlGF in the intra-and intermolecular cross talk between the VEGF receptors Flt1 and Flk1","volume":"9","author":"Autiero","year":"2003","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1350-9462(02)00043-5","article-title":"Vascular endothelial growth factors and angiogenesis in eye disease","volume":"22","author":"Witmer","year":"2003","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Pitale, P.M., and Gorbatyuk, M.S. (2022). Diabetic retinopathy: From animal models to cellular signaling. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031487"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1097\/ICU.0000000000000472","article-title":"Recent clinically relevant highlights from the diabetic retinopathy clinical research network","volume":"29","author":"Krick","year":"2018","journal-title":"Curr. Opin. Ophthalmol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7354\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T04:30:52Z","timestamp":1787113852000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7354"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,17]]},"references-count":32,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167354"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167354","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,17]]}}}