Sex Differences in IgG1-Mediated Inhibition of Choroidal Neovascularization

Sex differences significantly impact diseases involving angiogenesis, such as age- related macular degeneration (AMD), which is more prevalent in females. The basis for this sexual dimorphism is unknown. Using AMD as a disease and pathological angiogenesis model, this project explores the mechanisms underlying these contrasts, focusing on human IgG1, an endogenous anti-angiogenic protein, which is a treatment option for those experiencing various types of conditions classified as pathological angiogenesis and the influence of sex chromosomes and hormones on its activity. Human IgG1s possess intrinsic anti-angiogenic activity by suppressing macrophage chemotaxis, independent of their ability to bind antigens. Human and mouse models reveal that males exhibit stronger IgG1-induced chemotaxis inhibition and anti-angiogenic effects in choroidal neovascularization (CNV). The Y chromosome, particularly the DEAD-Box Helicase 3 Y-Linked (DDX3Y) gene, has been identified as crucial for these effects in males through gene and RNAi screening. The loss of this gene has been demonstrated to affect the response to IgG1 treatments in vitro and in vivo. Male mice and cells lacking Ddx3y exhibited blunted IgG1 responses in CNV and macrophage chemotaxis matching the responses observed in females. Estrogen is found to suppress IgG1-mediated angiogenesis inhibition, providing another possible explanation for the sexual dimorphic responses that have been observed in several models and systems. Removing estrogens or using estrogen receptor inhibitors enhance IgG1 responses in females, suggesting hormonal modulation as a therapeutic strategy. Additionally, voluntary exercise is shown to reduce CNV in mice, with a 41% decrease observed in trained mice, in comparison to sedentary mice highlighting the potential of lifestyle interventions as a cost-effective treatment option or prevention medicine. These findings provide new insights into sex-specific angiogenic mechanisms, with implications for treating AMD and other sex-related disorders.