title: Evidence implicating peroxisome proliferator-activated receptor-γ in the pathogenesis of preeclampsia.
abstract: Preeclampsia, a major cause of maternal and perinatal mortality and morbidity, is thought to be attributed, in part, to impaired trophoblast invasion. Peroxisome proliferator-activated receptors are ligand-activated transcription factors expressed in trophoblasts, which regulate the expression of a number of genes involved in cell differentiation and proliferation. We investigated the effect of the administration of a peroxisome proliferator-activated receptor-γ antagonist during uncomplicated pregnancy in rats. Using an intraperitoneal miniosmotic pump, healthy pregnant rats were administered either vehicle or the peroxisome proliferator-activated receptor-γ-specific antagonist, T0070907 (1 mg/kg per day from gestational days 11-15). Rats treated with T0070907 developed key features of preeclampsia, including elevated mean arterial blood pressure, proteinuria, endothelial dysfunction, reduced pup weight, and increased platelet aggregation. T0070907-treated rats had reduced plasma vascular endothelial growth factor and increased plasma soluble fms-like tyrosine kinase 1. Furthermore, increases in total placental soluble fms-like tyrosine kinase 1 mRNA and fms-like tyrosine kinase 1 protein were also demonstrated, suggesting the placenta as the main contributor to the increased circulating levels of soluble fms-like tyrosine kinase 1. The labyrinthine trophoblast in the placentas of T0070907-treated rats were less differentiated, had increased cellular proliferation, and were strongly immunopositive for CD-31 staining, indicating adaptive angiogenesis. The present study suggests that peroxisome proliferator-activated receptor-γ may play a pivotal role in the progression of a healthy pregnancy and may critically regulate the risk of preeclampsia. These findings have important implications regarding the underlying etiology of preeclampsia and potential therapeutic targets.
authors.affiliation: Anu Research Centre, Department of Obstetrics and Gynaecology, University College Cork, Cork, Ireland. fergusmccarthy@gmail.com
authors.forename: Fergus P
authors.initials: FP
authors.lastname: McCarthy
authors.forename: Sascha
authors.initials: S
authors.lastname: Drewlo
authors.forename: Fred A
authors.initials: FA
authors.lastname: English
authors.forename: John
authors.initials: J
authors.lastname: Kingdom
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Johns
authors.forename: Louise C
authors.initials: LC
authors.lastname: Kenny
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Walsh
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010974:Platelet Aggregation; D011225:Pre-Eclampsia / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D011247:Pregnancy; D011270:Pregnancy, Animal; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D018709:Statistics, Nonparametric; D016482:Urinalysis; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
chemical_list: D047495:PPAR gamma; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1