Relationship between gene expression and function of uterotonic systems in the rat during gestation, uterine activation and both term and preterm labour

Abstract

We have documented gestation-and labour-(preterm and term) dependent changes in expression of genes encoding contraction associated proteins in the rat uterus and correlated these changes with various parameters of uterine contractility. The data demonstrate increased expression of contractile agonist systems concurrent with decreased expression of relaxant systems after gestational day 20. Significant increases in expression of oxytocin (OT), its receptor (OTR), prostaglandin (PG) H synthase isoform 1 (PGHS-1) and PGF 2α receptor (FP) occurred first, followed by increases in PGHS-2, connexin-43, endothelin-1 (ET-1) and the ET-1 receptor isoform ET A . Expression of OTR and FP was significantly reduced during mid-gestation compared to non-pregnant animals. Expression of inducible nitric oxide synthase (iNOS) increased significantly during pregnancy then decreased concurrently with the increase in OTR and FP. Functional changes in uterine contractility accompany changes in gene expression. OT was the most potent contractile stimulant. Sensitivity of uterine strips to OT was reduced in early and mid-pregnancy then increased at uterine activation. Progesterone antagonist-induced preterm labour caused changes similar to those at normal term. Comparison of mRNA transcripts in separated endometrium and myometrium suggested that the endometrium is an important regulator of myometrial contractility, analogous to the relationship between endothelium and vascular smooth muscle. This novel combination of functional and genetic expression analyses provides new insight into the physiology of parturition.

Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia

“…Consistent with the concept of uterine quiescence during the course of pregnancy, we found that oxytocin contraction of myometrium strips was reduced in mid- and late-pregnant rats compared with virgin rats. Some studies have shown that oxytocin contraction of mid-term and late-pregnant uterus is greater than that in non-pregnant uterus, 378 which is opposite from our findings. This is likely because during late pregnancy the uterus is bigger and often thicker, and studies often measure uterine contraction in absolute grams.…”

“…Consistent with other reports in the rat uterus, 378,402 we have shown that oxytocin causes a steady increase in contraction and an additional spontaneous phasic contractile response. 93 [Ca 2+ ] I is a key regulator of uterine contraction.…”

A role of stretch-activated potassium currents in the regulation of uterine smooth muscle contraction

“…DHEA and DHEAS production in the fetus is thought to lead to initiation of parturition through their metabolism by the placenta to estrogen [9] , which acts on the myometrium, cervix and fetal membranes. While estrogen is thought to up-regulate the expression of myometrial genes associated with contraction [10] , it is progesterone that is thought to modulate parturition timing through its withdrawal. In a number of animal models, progesterone disappearance from the circulation is associated with onset [11] .…”

Preterm Birth: An Inflammatory Syndrome, Not Just A Myometrial Disorder

“…This leads to the production of pro-inflammatory cytokines and chemokines [33], extravasation of myeloid and lymphoid inflammatory cells (mostly neutrophils and monocytes/macrophages), and eventually, activation of many uterine activation proteins (UAPs). These UAPs promote cervical ripening, fetal membrane weakening, contractions and labor [34][35][36]. Importantly, data show that this inflammatory response does not resolve with birth [16], which may explain the inefficacy of tocolytics at improving neonatal outcomes.…”