Abstract 12079: The Sexual Dimorphism of IgG1 Anti-angiogenic Activity Depends on Y Chromosome Genes

Abstract

Section: Angiogenesis, Vascular Development and Regeneration Introduction: IgG1 antibodies possess sexually dimorphic anti-angiogenic activity independent of antigen binding. Mosaic loss of Y chromosome (LOY) is associated with numerous cardiovascular-related diseases, and the male specific region of the Y chromosome (MSY) contributes to hypertension, atherosclerosis, cancer, and male infertility. The biological mechanisms underlying these associations is largely unknown and not fully understood. A better understanding of the role of protein coding genes in the Y chromosome and angiogenesis regulation may lead to a better understanding of these associations and better treatments. Hypothesis: The loss of function of genes in the MSY of males impairs the anti-angiogenic activity IgG1 antibodies. Methods: MSY transcripts were quantified in human macrophages and primary bone marrow derived macrophages (BMDMs) from C57BL/6J male mice by qPCR. MSY genes were inhibited by siRNAs targeting DDX3Y, KDM5D, and UTY, followed by treatment with a human IgG1 in a chemotaxis assay. Laser photocoagulation-induced choroidal neovascularization (CNV) was performed in male C57BL/6J followed by intravitreous injection of full-length humanized IgG1 antibody along with a cell-permeable siRNA scrambled control or siRNA targeting DDX3Y. Results: Male macrophages from human and mouse transcribe multiple Y chromosome genes. Silencing of multiple MSY-encoded genes abrogated the ability of IgG1 to suppress chemotaxis and angiogenesis, rendering male systems to respond similarly to female systems. Male macrophages from DDX3Y knockout mice were also resistant to IgG1 treatment. siRNA targeting DDX3Y suppressed inhibition in male mice. Conclusions: The antiangiogenic activity IgG1 antibodies is greatly reduced by antagonizing Y chromosome genes. These studies highlight protein coding genes of the Y chromosome as a potential angiogenesis modulating target responsible for sexually dimorphic responses.