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Biosci. (Landmark Ed)"],"abstract":"<jats:p>Background: Platelet factor 4 (PF4\/CXCL4) is a chemokine with reported anti-angiogenic and immunomodulatory properties; however, the role of PF4 in neovascular age-related macular degeneration (nAMD) remains unclear. Thus, this study aimed to evaluate the therapeutic potential of PF4 in experimental models of ocular pathological neovascularization and explored the underlying mechanisms. Methods: PF4 expression was assessed in a laser-induced choroidal neovascularization (CNV) mouse model using quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunofluorescence. Recombinant PF4 was administered intravitreally in laser-induced CNV mice and very low-density lipoprotein receptor knockout (Vldlr\u207b\/\u207b) mice, a model of spontaneous retinal neovascularization with retinal angiomatous proliferation (RAP)-like lesions. Pathological neovascularization and vascular leakage were quantified by fundus fluorescein angiography and choroidal\/retinal flat-mount analyses. Immunofluorescence, qRT-PCR, and RNA sequencing were employed to evaluate inflammatory responses. Moreover, the effects of PF4 on vascular endothelial growth factor (VEGF)-induced proliferation, migration, and tube formation of human retinal microvascular endothelial cells were examined in vitro, and VEGF-mediated signaling was analyzed by Western blotting. Ocular safety was assessed by optical coherence tomography (OCT), electroretinography (ERG), hematoxylin and eosin (H&amp;E) staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Results: Intravitreal PF4 significantly reduced pathological neovascularization and vascular leakage in both models and attenuated intraocular inflammation, as indicated by decreased expression of proinflammatory cytokines and reduced microglial\/macrophage recruitment. PF4 inhibited VEGF-induced endothelial cell proliferation, migration, and tube formation in vitro. Mechanistically, PF4 downregulated VEGF expression in CNV lesions in vivo and suppressed VEGF-induced activation of vascular endothelial growth factor receptor 2 (VEGFR2) and downstream extracellular signal-regulated kinase (ERK), protein kinase B (AKT), and signal transducer and activator of transcription 3 (STAT3) signaling in vivo and in vitro. PF4 administration was well tolerated, with no detectable adverse effects on retinal structure or function. Conclusions: PF4 effectively inhibits ocular pathological neovascularization and inflammation by modulating the VEGF\/VEGFR2 signaling pathway. These findings support PF4 as a promising therapeutic candidate for nAMD and warrant further investigation.<\/jats:p>","DOI":"10.31083\/fbl49564","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T09:29:27Z","timestamp":1777454967000},"source":"Crossref","is-referenced-by-count":0,"title":["Platelet Factor 4: A Novel Therapeutic Inhibitor for Experimental Neovascular Age-Related Macular Degeneration"],"prefix":"10.31083","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3664-5712","authenticated-orcid":true,"given":"Xiubin","family":"Ke","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Tianjin Medical University General Hospital, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Ocular Trauma, Laboratory of Molecular Ophthalmology, Tianjin Medical University, 300070 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9821-8934","authenticated-orcid":true,"given":"Shuqi","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, School of Medicine, Nankai University, 300071 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7502-7437","authenticated-orcid":true,"given":"Tianhao","family":"Qu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tianjin Medical University General Hospital, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Ocular Trauma, Laboratory of Molecular Ophthalmology, Tianjin Medical University, 300070 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5957-5921","authenticated-orcid":true,"given":"Shenyu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tianjin Medical University General Hospital, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Ocular Trauma, Laboratory of Molecular Ophthalmology, Tianjin Medical University, 300070 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0620-8930","authenticated-orcid":true,"given":"Ji","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tianjin Medical University General Hospital, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Ocular Trauma, Laboratory of Molecular Ophthalmology, Tianjin Medical University, 300070 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8929-4706","authenticated-orcid":true,"given":"Han","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tianjin Medical University General Hospital, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Ocular Trauma, Laboratory of Molecular Ophthalmology, Tianjin Medical University, 300070 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7829-6935","authenticated-orcid":true,"given":"Yingying","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Tianjin Medical University, 300070 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6076-2547","authenticated-orcid":true,"given":"Man","family":"Xing","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Tianjin Medical University, 300070 Tianjin, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8628-243X","authenticated-orcid":true,"given":"Xiaohong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Tianjin Medical University General Hospital, International Joint Laboratory of Ocular Diseases (Ministry of Education), State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Ocular Trauma, Laboratory of Molecular Ophthalmology, Tianjin Medical University, 300070 Tianjin, China"},{"name":"Department of Pharmacology, Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, 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