ANGPTL4 Induces Aberrant Lymphatic-like Remodeling in Proliferative Diabetic Retinopathy

Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults and often progresses to proliferative diabetic retinopathy (PDR) with irreversible complications. While anti-vascular endothelial growth factor (VEGF) therapy remains the first-line treatment, resistance poses a significant challenge, necessitating alternative therapeutic targets. This study explores the role of angiopoietin-like protein 4 (ANGPTL4) in PDR pathogenesis, emphasizing vascular-immune-lymphatic interactions. We found significantly elevated ANGPTL4 and VEGF-C levels in the vitreous humor of PDR patients, which were not affected by anti-VEGF therapy. In vivo, full-length ANGPTL4 and its C-terminal fragment promoted pathological angiogenesis and lymphatic-like remodeling in diabetic murine retinas, characterized by increased lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), prospero homeobox 1 (PROX1) and VEGF receptor 3 (VEGFR3) expression. Single-cell sequencing further revealed ANGPTL4-driven immune dysregulation, with abnormal infiltration of CD4+ T cells and dendritic cells. Knockdown of ANGPTL4 in oxygen-induced retinopathy (OIR) mice alleviated retinal hypoxia, neovascularization, and vascular leakage. Mechanistically, retinal hypoxia markedly increased ANGPTL4 expression levels in the retina, which activated the activator protein-1 (AP-1) transcription factor complex and promoted Cd83 transcription in mouse heart microvascular endothelial cells (mHMECs). Additionally, ANGPTL4 bound to neuropilin-1 (NRP1)/VEGFR3, driving human lymphatic endothelial cells (hLECs) proliferation and lymphatic vessel ingrowth from the optic nerve sheath into the retina, suggesting a novel pathway independent of angiopoietin-Tie signaling. These findings establish ANGPTL4 as a key mediator of immune‒vascular interactions in PDR and a potential therapeutic target to address both pathological angiogenesis and lymphatic dysfunction.