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  • The uterine muscle also changes to meet the

    2023-09-28

    The uterine muscle also changes to meet the demands of pregnancy. Over the course of pregnancy, the myometrium undergoes structural remodeling to accommodate a growing fetus, followed by a functional switch from quiescent to contractile characteristics for parturition. Studies on the mouse model indicate that the myometrium first increases the number of Madecassic acid through proliferation at the early stage of pregnancy and then further expands in size via hypertrophy of the smooth muscle cells [2]. While uterine muscles remain noncontractile until full-term in normal pregnancy, myometrial contraction rises in response to increasing inflammatory pressure, fetal signals, and reorganization of molecules for coordinated muscle contraction during parturition 3, 4. Parturition occurring before 37 weeks of pregnancy is defined as preterm birth that risks serious health complications on underdeveloped babies. The fact that progesterone serves as an FDA-approved tocolytic agent to prevent premature parturition reveals its physiological significance in regulation of uterine contraction [5]. Meanwhile, progesterone has also been shown to promote the growth of muscle cells in the myometrium 6, 7. Collectively, this evidence indicates an indispensable role of progesterone in regulation of myometrial homeostasis. However, studies also suggest that the effectiveness of progesterone on preventing preterm birth remains inconclusive [5], which highlights the unknowns behind the action of the mechanism of progesterone. Progesterone action is primarily mediated by the progesterone receptor (PGR). In response to ligand stimulation, the PGR conveys extracellular signals to intracellular regulation of gene expression via its transcription factor capacity as well as its nongenomic activities [8]. The ability of the PGR to transduce progesterone signaling can be modulated by several layers of control, including transcriptional regulation of the PGR gene, post-translational modification of the PGR protein, stoichiochemistry of PGR isoforms, and interaction of PGR and coregulators on downstream targets 8, 9. Here we discuss the PGR-dependent genetic pathways that mediate progesterone signaling in the uterus, focusing on intercompartmental crosstalk in the endometrium at early pregnancy and the functional switch of PGR in the myometrium for parturition.
    The PGR-Dependent Pathway for Epithelium–Stroma Interaction in Endometrium Epithelium–stroma crosstalk prepares the endometrium for embryo implantation. In humans, PGR is transiently expressed in the luminal and glandular epithelium, peaking in the late proliferative and early secretory phase, followed by a sharp decease at the midsecretory phase [10]. In mice, PGR also exhibits a dynamic expression pattern in the uterine epithelium, where its messenger RNA levels start to rise at 1.5days postcoitum (dpc) and the protein amount reaches the maximum at 3.5 dpc 11, 12. Similar to humans, mouse epithelial PGR expression diminishes at 4.5 dpc before embryo implantation 11, 12. Studies on mouse models further reveal that increased PGR levels in the stroma surrounding implantation sites begin at the window of receptivity 11, 12, while transient stromal expression of PGR is observed in the human endometrium during the menstrual cycle [10]. The temporal dynamics of PGR expression are critical to prime and establish a receptive window for embryo implantation. Loss of or failure to decrease epithelial PGR expression in time has been shown to impede embryo implantation in mouse models 12, 13. Furthermore, dysregulated progesterone signaling, either by excessive levels of progesterone or constitutive PGR expression, have been shown to negatively impact the LIF pathway and result in failure Madecassic acid of embryo implantation 12, 14. These findings collectively suggest that dynamic PGR levels in endometria transduce the tightly orchestrated progesterone signaling during early pregnancy in an evolutionarily conserved manner.