Non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit prostaglandin synthase (PTGS) enzymes have been associated with increased miscarriage risk. While studies show diminished PTGS2-derived prostaglandins in the endometrium of patients with implantation failure, the role of PTGS2 during peri-implantation remains controversial in mouse models. Conflicting research suggests that PTGS2 knockout (Ptgs2-/-) mice show either comprehensive reproductive impairments or effects limited to ovulation. Furthermore, the specific uterine cell types involved in PTGS2 activity and its role in implantation chamber formation remain unclear. This thesis investigates prostaglandin's reproductive role through two complementary approaches in mouse models. First, we employed genetic deletion of PTGS2 in specific uterine cell types using multiple mouse models: Ptgs2-/- (global deletion), Ltfcre/+; Ptgs2f/f (uterine epithelial deletion), Pax2cre/+; Ptgs2f/f (uterine epithelial and endothelial deletion), and Pgrcre/+; Ptgs2f/f (deletion in ovary, oviduct, uterine epithelium, stroma, and circular smooth muscle). Second, we used pharmacological inhibition through NSAIDs: Aspirin (PTGS1-specific), Dup-697 (PTGS2-specific), and indomethacin (PTGS1 and PTGS2 inhibitor). Both approaches were enhanced by three-dimensional (3D) imaging techniques to evaluate uterine tissue remodeling during peri-implantation. Using tissue-specific knockout models, we demonstrate in Chapter 3 that deletion of PTGS2 in uterine stroma using Pgrcre/+; Ptgs2f/f impairs multiple reproductive processes: timely embryo implantation, post-implantation embryonic development, implantation chamber formation, vascular remodeling, decidualization, and overall pregnancy success. In contrast, epithelial and endothelial PTGS2 deletion shows no significant impact on these processes. Our analysis of NSAID effects in Chapter 4 reveals critical timing windows for PTGS activity during pregnancy establishment. Specifically, indomethacin treatment results in delayed implantation, disrupted embryo spacing, restricted embryonic growth, impaired implantation chamber formation, and vascular remodeling. These findings advance our understanding of prostaglandin signaling regulation during early pregnancy with important clinical implications. Understanding the cell type-specific and temporal requirements for prostaglandin signaling could help resolve controversies surrounding NSAID use during pregnancy and guide the development of safer anti-inflammatory therapy protocols. Additionally, variations in prostaglandin signaling across populations may explain differential susceptibility to implantation failure, highlighting the importance of personalized care approaches for optimal pregnancy outcomes.
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