INHIBITION OF UTERINE CONTRACTIONS BY FETAL MEMBRANES

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The purpose of this proposal is to study the role of human fetal membrane inhibitory systems in the control of uterine contractions with the long term goal of understanding the basic mechanisms involved in the initiation of labor. The biological mechanisms that maintain uterine quiicscence throughout most of pregnancy and cause the transition to labor at term are not clearly understood. The fetal membranes, the amjiion and chorion, and the maternal decidua are thought to be important in paracrine signalling and control of uterine contractions, cervical dilation and birth. The fetal membranes are interposed between the fetus and maternal decidua and uterine muscle. Thus, they are ideally positioned to regulate signal1ing between mother and fetus at the time of initiation of labor. Past research efforts by many investigators focused on stimulators of uterine contractions released from fetal membranes. Recently, we developed a dual chamber-fetal membrane-uterine muscle in vitro model to study the interactions of fetal membranes, maternal decidua and uterine muscle. In this system, fetal membranes are sealed into a Plexiglass chamber so that each hemichamber is a compartment for either the fetal or maternal side. A uterine muscle strip is added to the maternal side. Thus, effects of fetal membranes on the uterus can be assessed directly by measuring changes in uterine contractions. All components of the system, fetal membranes, maternal side signals and the uterine muscle model can be easily manipulated in this in vitro system. In recently published work, we unexpectedly found that human, term, labored fetal membranes inhibit spontaneous uterine contractions, that this inhibition is reversible and that the inhibitory effect is specific to the chorion/decidual side because membranes mounted with the amnion side toward the muscle did not show inhibition. This has changed the focus of our research efforts from stimulatory to inhibitory systems which are present in fetal membranes. Furthermore, preliminary data shown in this proposal suggests that the fetal membrane factor is able to inhibit BAY K8644 (a L-type calcium channel agonist) induced uterine contractions. These data lead to the proposed hypothesis that the fetal membrane inhibitor is an endogenous calcium channel antagonist. Fetal membrane inhibitory substances have potential as important regulators in the initiation of labor as well as potential as new therapies in the treatment of labor initiation abnormalities such as preterm labor. This revised FIRST grant application proposes a series of experiments to assign a mechanism of action for the fetal membrane factor as an endogenous calcium channel inhibitor, and establish the significance of the fetal membrane inhibitor to the onset of labor.