Anu Research Centre, Department of Obstetrics and Gynaecology, University College Cork, Cork, Ireland.
Hypertension. 2011 Nov;58(5):882-7. doi: 10.1161/HYPERTENSIONAHA.111.179440. Epub 2011 Sep 19.
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.
子痫前期是孕产妇和围产儿发病率和死亡率的主要原因之一，部分原因被认为是滋养细胞侵袭受损。过氧化物酶体增殖物激活受体是在滋养细胞中表达的配体激活转录因子，它调节许多参与细胞分化和增殖的基因的表达。我们研究了在正常妊娠的大鼠中给予过氧化物酶体增殖物激活受体-γ拮抗剂的效果。使用腹膜内微量渗透泵，给健康妊娠大鼠给予载体或过氧化物酶体增殖物激活受体-γ特异性拮抗剂 T0070907（从妊娠第 11-15 天每天 1mg/kg）。用 T0070907 处理的大鼠发展为子痫前期的主要特征，包括平均动脉血压升高、蛋白尿、内皮功能障碍、胎儿体重减轻和血小板聚集增加。T0070907 处理的大鼠血浆血管内皮生长因子降低，血浆可溶性 fms 样酪氨酸激酶 1 增加。此外，还证明总胎盘可溶性 fms 样酪氨酸激酶 1mRNA 和 fms 样酪氨酸激酶 1 蛋白增加，表明胎盘是增加循环可溶性 fms 样酪氨酸激酶 1 水平的主要来源。T0070907 处理大鼠的胎盘绒毛膜滋养细胞分化较少，细胞增殖增加，对 CD-31 染色呈强烈免疫阳性，表明适应性血管生成。本研究表明过氧化物酶体增殖物激活受体-γ可能在健康妊娠的进展中发挥关键作用，并可能严重调节子痫前期的风险。这些发现对子痫前期的潜在病因学和潜在治疗靶点具有重要意义。
