Center for the Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States; Molecular and Developmental Biology Graduate Program, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States; Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States
Maddison L Johnson
Department of Biological Sciences, Vanderbilt University, Nashville, United States
Julie Baker Phillips
Department of Biological Sciences, Vanderbilt University, Nashville, United States
Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States
Jeanne M James
The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States
Helen N Jones
Molecular and Developmental Biology Graduate Program, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States
Raymond W Redline
Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, United States
Department of Biological Sciences, Vanderbilt University, Nashville, United States
Louis J Muglia
Center for the Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, United States; Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States
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.
