Peer-Reviewed Journal Details
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McCarthy, FP,Drewlo, S,English, FA,Kingdom, J,Johns, EJ,Kenny, LC,Walsh, SK
2011
January
Hypertension
Evidence Implicating Peroxisome Proliferator-Activated Receptor-gamma in the Pathogenesis of Preeclampsia
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peroxisome proliferator activated receptor-gamma T0070907 preeclampsia vascular dysfunction INTRAUTERINE GROWTH RESTRICTION PPAR-GAMMA HEME OXYGENASE-1 UTERINE PERFUSION HUMAN TROPHOBLAST EXPRESSION RAT PREGNANCY ALPHA BLOOD
58
882
447
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-gamma antagonist during uncomplicated pregnancy in rats. Using an intraperitoneal miniosmotic pump, healthy pregnant rats were administered either vehicle or the peroxisome proliferator-activated receptor-gamma-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-gamma 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. (Hypertension. 2011; 58: 882-887.). Online Data Supplement
DOI 10.1161/HYPERTENSIONAHA.111.179440
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