PROJECT SUMMARY Many diseases of excess, abnormal, or insufficient angiogenesis such as peripheral artery disease, neovascular age-related macular degeneration, solid tumors, peripheral artery disease, and heart failure exhibit sexual dimorphism with respect to risk factors, incidence, and optimal interventions. Despite widespread acknowledgement of these disparities, the molecular mechanisms that promote sex differences in vascular conditions are understudied. Studies from our lab established that human IgG1 (and the murine equivalents IgG2a/c) possess intrinsic anti-angiogenic activity which occurs independently of antigen binding. Instead, this activity is due to recognition of the Fc domain of IgG1 by the high-affinity activating receptor FcγRI in macrophages. We term this activity “antibody-dependent cell-mediated angioinhibition” (ADCAI). These findings suggest that ADCAI is an evolutionarily conserved, fundamental process that affects vascular remodeling in multiple tissue beds and physiologic states. Prompted by the NIH's Guidelines on Sex as a Biological Variable, we recently made several striking observations suggesting that female animals and female-derived cells exhibit markedly reduced ADCAI compared to males. These findings raise the intriguing possibility that sex disparities in vascular remodeling may arise from differences in ADCAI responses. However, the mechanisms responsible for ADCAI sex differences, and whether ADCAI disparities are conserved in humans are unknown. Here, I propose to further investigate the mechanisms underlying sexual dimorphism in ADCAI. Specifically, I will determine the role of the gene DDX3Y, which was identified as a potential mediator of ADCAI in an unbiased screen of Y chromosome encoded genes (Aim 1). I will also investigate the affects that gonadectomies have on ADCAI (Aim 2). In addition, I will test whether ADCAI sex differences are conserved in human macrophages and humanized Fc receptor mice (Aim 3). My central hypothesis is that sexual dimorphism of ADCAI is a conserved process that is potentiated by expression of DDX3Y in macrophages. This project will shed new light on the contrasts between the angiogenesis regulation between sexes, revealing new pathways and targets to modulate angiogenesis in a more personalized manner to improve therapeutic outcomes.