Abstract
Healthy pregnancy depends on proper placentation-including proliferation, differentiation, and invasion of trophoblast cells-which, if impaired, causes placental ischemia resulting in intrauterine growth restriction and preeclampsia. Mechanisms regulating trophoblast invasion, however, are unknown. We report that reduction of Inverted formin 2 (INF2) alters intracellular trafficking and significantly impairs invasion in a model of human extravillous trophoblasts. Furthermore, global loss of Inf2 in mice recapitulates maternal and fetal phenotypes of placental insufficiency. Inf2-/- dams have reduced spiral artery numbers and late gestational hypertension with resolution following delivery. Inf2-/- fetuses are growth restricted and demonstrate changes in umbilical artery Doppler consistent with poor placental perfusion and fetal distress. Loss of Inf2 increases fetal vascular density in the placenta and dysregulates trophoblast expression of angiogenic factors. Our data support a critical regulatory role for INF2 in trophoblast invasion-a necessary process for placentation-representing a possible future target for improving placentation and fetal outcomes.
Highlights
Implantation and placentation involve complex synchronization between the developing embryo and decidualization of the uterus
To determine if Inverted formin 2 (INF2) is necessary for transcytosis in Extravillous trophoblasts (EVTs) as in other cells (AndresDelgado et al, 2010; Madrid et al, 2010), we visualized intracellular localization of MAL2 and lymphocyte-specific protein tyrosine kinase (LCK) in vehicle- or knockdown siRNA-treated HTR-8/SVneo cells
MAL2 is dispersed throughout the cytoplasm in vehicle-treated HTR-8/SVneo cells with no change in localization after INF2 knockdown (Figure 2—figure supplement 2)
Summary
Implantation and placentation involve complex synchronization between the developing embryo and decidualization of the uterus. Extravillous trophoblasts (EVTs) differentiate from column cytotrophoblasts (CTBs), invade through the endometrium to the myometrium, and remodel decidual spiral arteries to form high-capacity, low-resistance vessels, supplying maternal blood to the lacunae surrounding the developing placental villi (Damsky et al, 1992; Red-Horse et al, 2004). Shallow invasion by EVTs and failed spiral artery remodeling yield peripheral vasoconstriction and high-resistance vessels thought to comprise the first stage of the development of preeclampsia (PE).
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