Spatiotemporally distinct roles of cyclooxygenase-1 and cyclooxygenase-2 at fetomaternal interface in mice

Embryo Implantation is crucial for ensuring a successful pregnancy outcome and subsequent child health. The Intrauterine environment during the perl-Implantation period shows drastic changes in gene expression and cellular metabolism in response to hormonal stimull and reciprocal communication with embryos. Here, we performed spatial transcriptomic analysis to elucidate the mechanisms underlying embryo Implantation. Transcriptome data revealed that lipid metabolism pathways, especially arachidonic acid-related (AA-related) ones, were enriched in the embryo-receptive luminal epithella. Cyclooxygenases (COXs), rate-limiting enzymes involved In prostaglandin production by AA, were spatiotemporally regulated in the vicinity of embryos during Implantation, but the role of each COX Isozyme In the uterus for successful pregnancy was unclear. We established uterine-specific COX2-knockout (UKO) and COX1/uterine COX2-double- KO (COX1/COX2-DKO) mice. COX2 UKO caused deferred Implantation with falled trophoblast Invasion, resulting in subfertility with reduced pregnancy rates and litter sizes. COX1/COX2 DKO Induced complete infertility, owing to abrogated embryo attachment. These results demonstrate that both isozymes have distinct roles during embryo Implantation. Spatial transcriptome and Ilpidome analyses revealed unique proflies of prostaglandin synthesis by each COX Isozyme and spatlotemporal expression patterns of downstream receptors throughout the endometrium. Our findings reveal previously unappreciated roles of COXs at the fetomaternal Interface to establish early pregnancy.