Inverted formin 2 regulates intracellular trafficking, placentation, and pregnancy outcome.

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 <i>Inverted formin 2</i> (<i>INF2)</i> alters intracellular trafficking and significantly impairs invasion in a model of human extravillous trophoblasts. Furthermore, global loss of <i>Inf2</i> in mice recapitulates maternal and fetal phenotypes of placental insufficiency. <i>Inf2</i>^-/- dams have reduced spiral artery numbers and late gestational hypertension with resolution following delivery. <i>Inf2</i>^-/- fetuses are growth restricted and demonstrate changes in umbilical artery Doppler consistent with poor placental perfusion and fetal distress. Loss of <i>Inf2</i> increases fetal vascular density in the placenta and dysregulates trophoblast expression of angiogenic factors. Our data support a critical regulatory role for <i>INF2</i> in trophoblast invasion-a necessary process for placentation-representing a possible future target for improving placentation and fetal outcomes.