Uterine stromal but not epithelial PTGS2 is critical for murine pregnancy success.

Abstract

The use of non-steroidal anti-inflammatory drugs that target prostaglandin synthase (PTGS) enzymes has been implicated in miscarriage. Further, PTGS2-derived prostaglandins are reduced in the endometrium of patients with a history of implantation failure. However, in the mouse model of pregnancy, peri-implantation PTGS2 function is controversial. Some studies suggest that Ptgs2 -/- mice display deficits in ovulation, fertilization and implantation, while other studies suggest a role for PTGS2 only in ovulation but not implantation. Further, the uterine cell type responsible for PTGS2 function and the role of PTGS2 in regulating implantation chamber formation are not known. To address this, we generated tissue-specific deletion models of Ptgs2. We observed that PTGS2 ablation from the epithelium alone in Ltf cre/+ ; Ptgs2 f/f mice and in both the epithelium and endothelium of the Pax2 cre/+ ; Ptgs2 f/f mice does not affect embryo implantation. Further, deletion of PTGS2 in the ovary, oviduct and uterus using Pgr cre/+ ; Ptgs2 f/f does not disrupt pre-implantation events but instead interferes with post-implantation chamber formation, vascular remodeling and decidualization. While all embryos initiate chamber formation, more than half of the embryos fail to transition from blastocyst to epiblast stage, resulting in embryo death and resorbing decidual sites at mid-gestation. Thus, our results suggest no role for uterine epithelial PTGS2 in early pregnancy but instead highlight a role for uterine stromal PTGS2 in modulating post-implantation embryo and implantation chamber growth. Overall, our study provides clarity on the compartment-specific role of PTGS2 and provides a valuable model for further investigating the role of stromal PTGS2 in post-implantation embryo development.