Preimplantation horse conceptuses require nutrients and signals from histotroph, the composition of which is regulated by luteal progesterone and conceptus-secreted factors. To distinguish progesterone and conceptus effects we shortened the period of endometrial progesterone-priming by asynchronous embryo transfer. Day 8 embryos were transferred to synchronous (day 8) or asynchronous (day 3) recipients, and RNA sequencing was performed on endometrium and conceptuses recovered 6 and 11 days later (embryo days 14 and 19). Asynchrony resulted in many more differentially expressed genes (DEGs) in conceptus membranes (3473) than endometrium (715). Gene ontology analysis identified upregulation in biological processes related to organogenesis and preventing apoptosis in synchronous conceptuses on day 14, and in cell adhesion and migration on day 19. Asynchrony also resulted in large numbers of DEGs related to 'extracellular exosome'. In endometrium, genes involved in immunity, the inflammatory response, and apoptosis regulation were upregulated during synchronous pregnancy and, again, many genes related to extracellular exosome were differentially expressed. Interestingly, only 14 genes were differentially expressed in endometrium recovered 6 days after synchronous versus 11 days after asynchronous transfer (day 14 recipient in both). Among these, KNG1 and IGFBP3 were consistently upregulated in synchronous endometrium. Furthermore bradykinin, an active peptide cleaved from KNG1, stimulated prostaglandin release by cultured trophectoderm cells. The horse conceptus thus responds to a negatively asynchronous uterus by extensively adjusting its transcriptome, whereas the endometrial transcriptome is modified only subtly by a more advanced conceptus.Int. J. Mol. Sci. 2020, 21, 2562 2 of 25 to be essential for MRP, since restricting migration to a single uterine horn results in failure to avert luteolysis [7]. In the absence of pregnancy, luteolysis occurs between approximately days 13 and 16 as a result of pulses of prostaglandin F2α (PGF2α) released by the endometrium following the establishment of an oxytocin-PGF2α positive feedback loop [8,9]. To prevent luteal regression, the embryo's MRP signal must prevent the cyclical increase in oxytocin sensitivity that starts at approximately day 10 after ovulation [10,11]. Although the identity of the equine embryonic MRP signal(s) remains unknown [12], it is increasingly clear that MRP involves the transient suppression of PGF2α release by a combination of inhibiting prostaglandin-endoperoxidase-synthase 2 expression (PTGS2; the rate-limiting enzyme in PGF2α synthesis) and delaying the upregulation of the endometrial oxytocin receptors critical to the oxytocin-PGF2α loop needed to generate luteolytic pulses of PGF2α [8,10,13].Recent transcriptomic and proteomic analyses have improved our understanding of embryo-maternal communication during the conceptus migration and MRP phase. Studies have compared gene expression in endometrium between cycling and pregnant mares on days 8 an...