Systemic administration of a reported extracellular vesicle inhibitor, dimethyl amiloride, induces preterm birth and fetal growth restriction in pregnant mice.

Abstract

Successful pregnancy is dependent on extensive coordination between maternal, placental, and fetal units. Alterations in maternal-placental signaling or abnormal placental development can lead to a wide variety of pregnancy complications. This commonly includes preterm birth and fetal growth restriction, which are associated with a high rate of maternal and fetal morbidity and mortality. Maternal-placental signaling is in part mediated by the release of extracellular vesicles. These lipid-bilayer nanoparticles are secreted by various cell types and act as key regulators of both normal and pathogenic cell-cell communication. In a healthy pregnancy, maternal plasma extracellular vesicle concentrations increase as gestation progresses. However, in the pregnancy-associated disorder, preeclampsia, excessive extracellular vesicle secretion occurs and may be involved in the pathogenesis of the condition. Thus, there is a critical need - as a first step - to understand if modifying extracellular vesicle concentration, specifically during pregnancy can attenuate or exacerbate gestational pathogenesis. In this study, we evaluated the effects of administering a reported extracellular vesicle inhibitor, dimethyl amiloride, on maternal extracellular vesicle concentrations in healthy pregnant mice and assessed maternal and fetal outcomes. Maternal administration of dimethyl amiloride resulted in a significant decrease in maternal weight as well as fetal growth and substantially increased the rate of preterm birth. In contrast to previous reports in non-pregnant animals, we found that dimethyl amiloride did not significantly reduce maternal extracellular vesicle concentrations in pregnant mice. Our data demonstrate that systemic administration of dimethyl amiloride drastically impacts the mother and fetus during gestation and caution is suggested against its use during pregnancy.