Severe preeclampsia (sPE) is a placenta-based hypertensive disorder affecting 2 to 7% of all pregnancies. It is the leading cause of fetal and maternal morbidity and mortality worldwide. The Preeclampsia Foundation (2007) estimates the annual economic cost of sPE in the USA to be $7 billion. Presently, the only available cure for this disease is placental and fetal delivery. In severe cases, this disease leads to preterm birth which, in itself, has numerous serious long- term complications. The ultimate goal of this project is to improve pregnancy outcome by ameliorating placental and maternal endovascular function in severe preeclampsia. sPE placentas are characterized by abnormal trophoblast differentiation, which, together with reduced uteroplacental perfusion, results in a hypoxic state leading to abnormal placental secretion of proteins, which in turn contribute to maternal vascular dysfunction, proteinuria and hypertension. The transcription factor and nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPAR?), has recently been found to regulate the transcription factor GCM1, which regulates trophoblast differentiation and is reduced in sPE. PPAR? can be manipulated by drugs of the thiazolidinedione class, which are normally used for the treatment of type II diabetes. Using Rosiglitazone in a rat model of sPE, we have shown great improvements in pregnancy outcome and maternal vascular function. We hypothesize that human trophoblast differentiation is regulated by the PPAR?-GCM1 axis and that it can be induced pharmacologically to improve placental and, in turn, maternal endothelial function. Furthermore, we challenge the current tenet that pathological protein secretion in preeclampsia is primarily caused by hypoxia, and suggest instead that it is driven by abnormal differentiation. This hypothesis will be critically tested by completing the following three specifc aims; 1. We will assess whether PPAR? regulates human trophoblast differentiation by direct regulation of the transcription factor GCM1 as part of a cascade that in turn regulates many other proteins. 2. We will test whether modulation of PPAR? activity will improve placental function in a hypoxic placental explant model of sPE. 3. We will determine whether placental protein secretion can be altered through modulation of PPAR? activity to drive trophoblast differentiation, and whether this, in turn, will improve maternal endothelial function. The efficac of this strategy will be assessed by determining in an angiogenesis assay whether media from pathological tissues treated with PPAR? activating drugs will improve endothelial function. Successful completion of this study will explain new pathways in human placental development and the pathophysiology of preeclampsia.

Public Health Relevance

This project addresses the important issue of preeclampsia, a pregnancy-related, hypertensive disorder that is the leading cause of fetal and maternal death worldwide. At present, there is no cure for preeclampsia other than placental delivery. We recently discovered a novel signaling pathway within the placenta, which, when altered with a drug normally used to treat type II diabetes, can restore placental function. We will test the hypothesis that drug treatment of pathological placental tissue will improve placental, as well as maternal vascular, function, while not adversely affecting other tissue. Successful completion of this project will provide the foundation of a treatment option that improves fetal and maternal health during pregnancy and beyond.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Mcdonald, Cheryl
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Michigan State University
East Lansing
United States
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Bolnick, Alan D; Bolnick, Jay M; Kohan-Ghadr, Hamid-Reza et al. (2018) Nifedipine Prevents Apoptosis of Alcohol-Exposed First-Trimester Trophoblast Cells. Alcohol Clin Exp Res 42:53-60
Kadam, Leena; Gomez-Lopez, Nardhy; Mial, Tara N et al. (2017) Rosiglitazone Regulates TLR4 and Rescues HO-1 and NRF2 Expression in Myometrial and Decidual Macrophages in Inflammation-Induced Preterm Birth. Reprod Sci 24:1590-1599
Bolnick, Alan D; Bolnick, Jay M; Kohan-Ghadr, Hamid-Reza et al. (2017) Enhancement of trophoblast differentiation and survival by low molecular weight heparin requires heparin-binding EGF-like growth factor. Hum Reprod 32:1218-1229
Drewlo, Sascha; Armant, D Randall (2017) Quo vadis, trophoblast? Exploring the new ways of an old cell lineage. Placenta 60 Suppl 1:S27-S31
Xu, Yi; Romero, Roberto; Miller, Derek et al. (2016) An M1-like Macrophage Polarization in Decidual Tissue during Spontaneous Preterm Labor That Is Attenuated by Rosiglitazone Treatment. J Immunol 196:2476-2491
St Louis, Derek; Romero, Roberto; Plazyo, Olesya et al. (2016) Invariant NKT Cell Activation Induces Late Preterm Birth That Is Attenuated by Rosiglitazone. J Immunol 196:1044-59
Bolnick, Alan D; Fritz, Rani; Jain, Chandni et al. (2016) Trophoblast Retrieval and Isolation From the Cervix for Noninvasive, First Trimester, Fetal Gender Determination in a Carrier of Congenital Adrenal Hyperplasia. Reprod Sci 23:717-22
Bolnick, Jay M; Kohan-Ghadr, Hamid-Reza; Fritz, Rani et al. (2016) Altered Biomarkers in Trophoblast Cells Obtained Noninvasively Prior to Clinical Manifestation of Perinatal Disease. Sci Rep 6:32382
Jain, Chandni V; Kadam, Leena; van Dijk, Marie et al. (2016) Fetal genome profiling at 5 weeks of gestation after noninvasive isolation of trophoblast cells from the endocervical canal. Sci Transl Med 8:363re4
Fritz, Rani; Kohan-Ghadr, Hamid-Reza; Bolnick, Jay M et al. (2015) Noninvasive detection of trophoblast protein signatures linked to early pregnancy loss using trophoblast retrieval and isolation from the cervix (TRIC). Fertil Steril 104:339-46.e4

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