Every year over 300,000 women die from pregnancy complications, and over 6.5 million more suffer complications that result in life-long disability, for which $41 billion is spent on healthcare costs. However, little is known about the development and differentiation of the cells?extravillous trophoblasts (EVTs)?at the heart of most human pregnancy complications. Our overarching goal is to develop mechanism-based strategies to prevent, diagnose, and treat pregnancy complications associated with faulty trophoblast development. We have strong evidence that vascular endothelial growth factor (VEGF) acts directly on trophoblast stem cells and plays a key role in the differentiation of junctional zone cells and specific subtypes of trophoblast giant cells (TGCs) in mice, which are orthologous to EVTs in humans. We discovered that different levels of decidual VEGF overexpression at the implantation site stimulates placental production of the potent endogenous VEGF antagonist soluble fms-like tyrosine kinase 1 (sFlt1) and induces a spectrum of symptoms in mice similar to those of human obstetrical diseases, from preeclampsia to abruptio placentae. Our preliminary data show that specific symptoms of each of those diseases are associated with abnormal development of a subset of TGCs and junctional zone cells. Thus, we hypothesize that the level of VEGF overexpression during early placental development corresponds to abnormal development of specific subtypes of TGCs associated with distinct pregnancy complications and that the diseases associated with excess sFlt1 production can be treated by reducing sFlt1 only at later stages of pregnancy. We also hypothesize that different EVT subtypes exist and that excess VEGF can cause disproportionate expansion of specific EVT subtypes in humans. Thus, our experiments will define the role of VEGF in the development of specific trophoblast subtypes (Aim 1), how levels of VEGF affect these cells at each stage of placental development in vivo in the mouse, how these cellular defects are related to specific pregnancy outcomes (Aim 2), and where and when VEGF signaling pathways can be targeted for prevention and therapeutic strategies (Aim 2). Several novel techniques will be used to address these questions, including inducible placenta- and decidua-specific gene expression systems for precise control of gene expression at discrete stages of pregnancy, and nanoparticle-mediated delivery of morpholinos to specific cells in the placenta. Finally, our preliminary data suggest that analogous EVTs may be present at similar locations in the human placenta as TGCs in mice and that VEGF may play a similar role in human trophoblast differentiation. We will characterize the diversity of EVTs in human placenta using laser microdissection, global transcriptional profiling, and a culture model of human chorionic trophoblast progenitor cell differentiation (Aim 3). These studies will characterize the previously unappreciated relationship between excess VEGF signaling and faulty trophoblast differentiation and the resulting spectrum of pregnancy disorders and provide specific guidance for the development of diagnostics and targeted therapies for these disorders.

Public Health Relevance

This study examines the molecular control of the development of placental trophoblasts, a process essential to normal pregnancy, and how aberrations in normal trophoblast development can lead to a spectrum of pregnancy disorders, from abruptio placentae to preeclampsia, common and life-threatening disorders. This work will specifically define how the angiogenesis regulator vascular endothelial growth factor (VEGF) regulates trophoblast differentiation and will define approaches for altering VEGF function at different stages of pregnancy to safely prevent or alleviate pregnancy complications. Thus, this work could have far-reaching effects on maternal and fetal health and help prevent both the acute and long-term health risks associated with pregnancy complications.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Ilekis, John V
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University of Missouri Kansas City
Kansas City
United States
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Zhang, Baozhen; Chen, Zhilong; Han, Jinyu et al. (2018) Comprehensive Evaluation of the Effectiveness and Safety of Placenta-Targeted Drug Delivery Using Three Complementary Methods. J Vis Exp :
Wheeler, Karen C; Jena, Manoj K; Pradhan, Bhola S et al. (2018) VEGF may contribute to macrophage recruitment and M2 polarization in the decidua. PLoS One 13:e0191040