Abstract
An incomplete understanding of the molecular mechanisms responsible for myometrial activation from the quiescent pregnant state to the active contractile state during labor has hindered the development of effective therapies for preterm labor. Myometrial stretch has been implicated clinically in the initiation of labor and the etiology of preterm labor, but the molecular mechanisms involved in the human have not been determined. We investigated the mechanisms by which gestation-dependent stretch contributes to myometrial activation, by using human uterine samples from gynecologic hysterectomies and Cesarean sections. Here we demonstrate that the Ca requirement for activation of the contractile filaments in human myometrium increases with caldesmon protein content during gestation and that an increase in caldesmon phosphorylation can reverse this inhibitory effect during labor. By using phosphotyrosine screening and mass spectrometry of stretched human myometrial samples, we identify 3 stretch-activated focal adhesion proteins, FAK, p130Cas, and alpha actinin. FAK-Y397, which signals integrin engagement, is constitutively phosphorylated in term human myometrium whereas FAK-Y925, which signals downstream ERK activation, is phosphorylated during stretch. We have recently identified smooth muscle Archvillin (SmAV) as an ERK regulator. A newly produced SmAV-specific antibody demonstrates gestation-specific increases in SmAV protein levels and stretch-specific increases in SmAV association with focal adhesion proteins. Thus, whereas increases in caldesmon levels suppress human myometrium contractility during pregnancy, stretch-dependent focal adhesion signaling, facilitated by the ERK activator SmAV, can contribute to myometrial activation. These results suggest that focal adhesion proteins may present new targets for drug discovery programs aimed at regulation of uterine contractility.
Highlights
In late pregnancy increasing fetal growth significantly increases uterine wall tension
Human myometrial CaD protein content and the [Ca2+] requirement for contractile activation increase during pregnancy h-Caldesmon (CaD) is a smooth muscle-specific actin binding protein that interferes with acto-myosin interactions [12]
Our data are consistent with the hypothesis that the observed increased inhibitory caldesmon protein content in human myometrium leads to a decreased contractile responsiveness to Ca during pregnancy
Summary
In late pregnancy increasing fetal growth significantly increases uterine wall tension. Compared to the nonpregnant uterus, human uterine weight increases from 70 grams to about 1100 grams at term pregnancy. Its total volume averages about 5000 ml, an expansion in size of approximately 250 fold [1]. No other smooth muscle organ in the human is able to stretch as much as the uterus. Myometrial stretch has been implicated, clinically, in the activation of the myometrium for labor, but the mechanisms involved are unclear. It is known that multiple gestation pregnancies and polyhydramnios, conditions associated with increased tension/stretch on the uterine wall, cause an increased incidence of premature labor. Understanding the molecular basis of uterine contraction will aid the better control and manipulation of uterine contractile function in preterm and dysfunctional labor
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