Microglia-Mediated Pathological Retinal Angiogenesis Leading to Visual Impairment in Mice Exposed to...

Increasing epidemiological evidence suggests that human visual impairment is associated with perfluoroalkyl and polyfluoroalkyl substances, although the underlying mechanisms remain unclear. In this study, we established a mouse model through a 28-day oral administration of perfluorooctanoic acid (PFOA) at doses of 3 and 15 mg/kg BW/day to investigate its impacts on pathological retinal angiogenesis, a hallmark of multiple vision-threatening diseases. PFOA exposure induced characteristic retinal acellular capillary formation, even in the normal avascular zone, accompanied by a hemorrhagic manifestation. Through integrated methodologies combining in vivo reactive oxygen species (ROS) quantification, retinal proteomics, and microglial phenotypic analysis, we demonstrated that PFOA compromises blood-retinal barrier integrity, resulting in ROS accumulation. This triggered a cascade involving nuclear factor-kappa B (NF-κB) activation, microglial proinflammatory response, proinflammatory cytokine release, cyclooxygenase-2 (COX-2) overexpression, and subsequent vascular endothelial growth factor A (VEGFA) hypersecretion. Complementary in vitro experiments further confirmed that PFOA treatment induced microglial activation by prompting NF-κB nuclear translocation, with activated microglia secreting VEGFA, which targets retinal microvascular endothelial cells to promote tube formation. Our work provides the first mechanistic insights into PFOA-induced retinal angiogenesis and highlights its potential role in visual impairment.