Frontiers in bioscience (Landmark edition) · 2026
Platelet Factor 4: A Novel Therapeutic Inhibitor for Experimental Neovascular Age-Related Macular Degeneration.
СтатьяНазвание и аннотация: Перевод в очереди
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Ke Xiubin, Liang Shuqi, Qu Tianhao, Li Shenyu, Lei Ji, Han Han, Guo Yingying, Xing Man, Wang Xiaohong, He Shikun, Liao Mengyu, Zhou Dongming, Yan Hua
Аннотация
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⁻/⁻) 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&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.
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⁻/⁻) 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&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.