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Original Articles

Evidence Implicating Peroxisome Proliferator-Activated Receptor-γ in the Pathogenesis of Preeclampsia

Fergus P. McCarthy, Sascha Drewlo, Fred A. English, John Kingdom, Edward J. Johns, Louise C. Kenny, Sarah K. Walsh
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https://doi.org/10.1161/HYPERTENSIONAHA.111.179440
Hypertension. 2011;HYPERTENSIONAHA.111.179440
Originally published September 19, 2011
Fergus P. McCarthy
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Sascha Drewlo
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Fred A. English
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John Kingdom
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Edward J. Johns
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Louise C. Kenny
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Sarah K. Walsh
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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.

  • peroxisome proliferator activated receptor-γ
  • T0070907
  • preeclampsia
  • vascular dysfunction
  • Received July 10, 2011.
  • Revision received July 29, 2011.
  • Accepted August 25, 2011.
  • © 2011 American Heart Association, Inc.
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    Evidence Implicating Peroxisome Proliferator-Activated Receptor-γ in the Pathogenesis of Preeclampsia
    Fergus P. McCarthy, Sascha Drewlo, Fred A. English, John Kingdom, Edward J. Johns, Louise C. Kenny and Sarah K. Walsh
    Hypertension. 2011;HYPERTENSIONAHA.111.179440, originally published September 19, 2011
    https://doi.org/10.1161/HYPERTENSIONAHA.111.179440

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    Evidence Implicating Peroxisome Proliferator-Activated Receptor-γ in the Pathogenesis of Preeclampsia
    Fergus P. McCarthy, Sascha Drewlo, Fred A. English, John Kingdom, Edward J. Johns, Louise C. Kenny and Sarah K. Walsh
    Hypertension. 2011;HYPERTENSIONAHA.111.179440, originally published September 19, 2011
    https://doi.org/10.1161/HYPERTENSIONAHA.111.179440
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