Abstract
Preterm labor is defined as the onset of regular uterine contractions associated with progressive cervical change that often leads to delivery before 37 weeks of gestation. Affecting approximately 5% to 10% of live births in the developed countries and significantly more in the developing world, prematurity due to preterm birth is estimated to be responsible for considerable infant morbidity and as much as 28% of neonatal mortality worldwide. 1,2 Tocolytic agents are drugs that have been shown both in vivo and in vitro to inhibit contractions of the myometrial smooth muscle cells that are often administrated to patients to prevent preterm delivery and the perinatal morbidity and mortality associated with preterm birth. 3 Currently available tocolytics are, however, not completely effective on achieving these goals and the need for novel, more successful therapeutic targets is undoubtable. Therefore, intense research on the topic has been performed resulting on several important publications. 4 –9 Accordingly, in the current issue of Reproductive Sciences, Danielsson and colleagues report their findings on the anoctamin family and its impact on the uterine smooth muscle contractions. 10
Anoctamins (ANO) are a family of calcium-activated chloride channels, from which a subset has been previously shown to be involved in procontractile depolarizing membrane currents leading to contraction of murine uterine smooth muscle cells. The blockage of these channels, specifically ANO1 and ANO2, has also been demonstrated to relax the uterine contractions in the rodent, but the role of ANO in the human late gestation has not been previously evaluated. In the current report, Danielsson and colleagues aimed to investigate this further by determining the expression profiles of the anoctamin family in the human uterine smooth muscle and by blocking ANO1/2 to assess whether it could suppress human uterine smooth muscle contractility and pacing frequency. 10,11
In order to determine which members of the ANO family are expressed in the human uterine smooth muscle, the authors used RT-PCR, qRT-PCR, and immunohistochemical staining. In addition, Danielsson and colleagues used an organ bath to study the effect of ANO1 antagonists on oxytocin-induced uterine smooth muscle contractions. Furthermore, ANO1 siRNA knockdown was performed to determine its effect on filamentous/globular actin ratio, a measurement of actin polymerization’s role in promoting smooth muscle contraction.
Results showed that mRNA encoding all members of the ANO family (except ANO7) is detectable in pregnant human uterine smooth muscle tissue. Interestingly, the authors observed that ANO1 mRNA expression was decreased 15.2 fold in pregnant tissue as compared to the nonpregnant and that the ANO1 protein was expressed in pregnant human uterine smooth muscle tissue. Functional organ bath studies with pregnant human uterine smooth muscle tissue also demonstrated that the ANO1 antagonist benzbromarone attenuates the force and frequency of oxytocin-induced contractions. Finally, siRNA knockdown of ANO1 evidenced a decrease in filamentous/globular actin ratios.
In sum, the results obtained by Danielsson et al evidence that multiple members of the ANO family, including the calcium-activated chloride channel ANO1, are expressed in human uterine smooth muscle cells. Moreover, their findings demonstrate that antagonism of ANO1 by pharmacological inhibition and genetic knockdown leads to an attenuation of contractions in the pregnant human uterine smooth muscle tissue. Thus, altogether, the findings presented by Danielsson and colleagues suggest that ANO1 is a potentially novel target for tocolysis that may prove more efficient than the currently available ones to treat preterm labor and to prevent preterm birth.