The role of Ras-related C3 botulinum toxin substrate 1 (RAC1)-dependent pathway in the regulation of uterine function during early pregnancy

During implantation, uterine stromal cells differentiate into specialized decidual cells, which become secretory and support the growth of the embryo before placentation. At the same time, new blood vessels begin to form in the maternal decidua from pre-existing vasculature. This process termed angiogenesis is critical for the establishment of the placenta and the maintenance of pregnancy. Although it is clear that decidualization and angiogenesis play a crucial role during early pregnancy, the complex molecular pathways underlying these processes remain largely unknown. Our recent studies revealed that RAC1 (Ras-related C3 botulinum toxin substrate 1), a pleiotropic signaling factor belonging to the Rho family of GTPases, is induced in the uterine stroma during decidualization and angiogenesis, suggesting a role for RAC1 in these critical processes. To address the role of RAC1 during pregnancy, we created a conditional knockout of the Rac1 gene in the uterus by crossing mice carrying floxed Rac1 with PgrCre mice, thereby generating the conditional mutation termed as Rac1d/d. A six-month breeding study indicated a severe defect in fertility of the Rac1d/d females. Further analysis revealed that while embryo attachment appeared to be unaffected, differentiation and secretory functions of decidual cells were impaired in Rac1d/d uteri. This abnormality of decidual cells led to multifactorial consequences, including compromised uterine vascular remodeling and angiogenesis, maternal blood vessel hemorrhage and placental abnormalities resulting in embryo loss around days 10 to 12 of pregnancy. Fetuses that survived to day 15 of pregnancy showed indications of intrauterine growth restriction. Based on the results obtained in this dissertation, we propose that RAC1 regulates stromal differentiation and secretory functions, which produce and secrete critical local factors that regulate vascular remodeling at the maternal-fetal interface and promote proper formation of the placental disk. Therefore, RAC1 induced in the uterine stroma during decidualization plays a critical role in maintaining proper function of the placental vascular bed and supporting embryo growth and development during early and mid-stages of pregnancy