Glucocorticoids and proteases in the pathophysiology of pregnancy and parturition

Understanding the physiology of pregnancy and parturition enables effective management of pregnancy complications that could otherwise be life threatening for both mother and fetus. A large body of evidence suggests that glucocorticoids (GC) and matrix metalloproteinases (MMPs) play a key role in the pathophysiology of pregnancy and parturition. Glucocorticoids influence several aspects of embryo implantation process including the maternal immune response, embryo attachment and fetal development. Prolonged exposure to high levels of glucocorticoids in pregnancy is dangerous for both placental and fetal development indicating that tight control of GC levels at the fetal-maternal interface is essential for establishment and maintenance of a healthy pregnancy. GC exert their actions via the glucocorticoid receptor, an ubiquitously expressed nuclear receptor comprised of 9 exons. Previous studies have demonstrated that differential promoter usage and alternative splicing-generated GR mRNA transcripts result in differential cellular GC responses. Matrix metalloproteinases are involved in the extracellular matrix remodeling and they contribute to the success of a pregnancy from embryo implantation to labour and postpartum involution. A misregulation of their expression or their activity is observed in adverse outcomes of pregnancy such as preterm labour. The aim of this thesis was to investigate 1) the expression of GR transcripts and the effect of inflammatory cytokines on the control of GR transcripts expression in cultured first trimester human decidua cells; 2) the expression of the two major groups of MMPs (stromelysins and gelatinases) and their inhibitors TIMP-1 and TIMP-2 in a) the mouse uterus throughout normal gestation, at labour and during inflammation-induced preterm birth and b) the human myometrium at term and preterm, both non-labouring and labouring. This study demonstrated that first trimester human decidua cells are characterized by a complex pattern of GR mRNA transcripts expression. Among the several GR isoforms expressed, GRβ, GRγ, GRP and GRα-D might be correlated with the development of the glucocorticoid resistance. Moreover, the significant increase in GR isoforms mRNA expression and protein levels observed in IL-1β or TNF-α- treated FT-DCs suggest a role for inflammatory cytokines in regulating decidual GR isoforms abundance. Furthermore, this study demonstrated that the majority of MMPs (Mmp-3, Mmp-2, Mmp-9, Mmp-10) studied in the mouse uterus displayed higher expression in early gestation compared to late gestation and labour; only Mmp-10 exhibited increased expression at labour suggesting a role in parturition. In addition, Mmp-3 and Timp-1 increased in the uterus of mice destined to undergo premature labour due to LPS-induced intrauterine inflammation, in contrast to Timp-2, which decreases. These observations may suggest a role of MMP-3 and TIMP-1 in preterm labor. Finally, this work reported a decreased expression of MMP-10 in the human myometrium with the onset of term, but notably not preterm labour. On the other hand, human TIMP-1 is dramatically increased with the onset of term and preterm labour. In conclusion, this study provide key novel findings in the pathophysiology of pregnancy and parturition highlighting 1) the importance of GCs and their receptors GRs in the establishing of pregnancy and that the identification, characterization and regulation of the several GR isoforms involved in the modulation of glucocorticoid action may lead to potential strategies for the treatment or prevention of a variety of pregnancy-related disorders; 2) the important involvement of MMPs and TIMPs in uterine remodeling during pregnancy and labour and that the balance between MMP and TIMP expression may be critical to controlling the timing of normal labour, alterations in MMP/TIMP ratio lead to multiple pregnancy complications such as preterm birth.