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.
Keywords: NF-κB; angiogenesis; microglia; perfluorooctanoic acid; retina.