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	VEGF Overexpression at Early Stages of Placental Development Leads to Expansion of the Spongiotrophoblast Layer andExcess sFlt1 Production – Relevance to Pathogenesis of Preeclampsia
	BHOLA PRADHAN; XIUJUN FAN; SABITA DHAL; Susan Fisher; NIHAR NAYAK
	2016
会议名称	Systems Biology of Reproduction SSR 49th Annual Meeting
会议地点	美国圣地亚哥
英文摘要	Preeclampsia is a major cause of maternal morbidity and mortality throughout the world, yet its pathogenesis is poorly understood. Recent studies show that excess vascular endothelial growth factor (VEGF) production throughout pregnancy can stimulate excess placental fms-like tyrosine kinase-1 (sFlt1) production and induce symptoms of preeclampsia. However, the mechanisms of sFlt1 overproduction in the placenta and the timing of this effect have not been clearly determined. In this study, by examining human placenta and placental bed biopsies from preeclamptic pregnancies and using a highly responsive placenta-specific, doxycycline (Dox)- inducible gene expression system in the mouse, we demonstrate that transient VEGF overexpression specifically in early placental development leads to symptoms of preeclampsia, identifying for the first time the mechanism and a critical stage in gestation when excess VEGF could cause symptoms of preeclampsia. Placental bed biopsies from the center of the placenta and full-thickness placental samples were collected from preeclamptic and gestational age-matched normal subjects undergoing cesarean section delivery (n=10). Expression and cellular localization of splice variants of human sFlt1 (sFlt1-i13 and sFlt1-e15a) were analyzed by qRT-PCR and in situ hybridization (ISH). sFlt1-e15a mRNA was found to be more abundant than sFlt1-i13 in both villous and extravillous trophoblasts (EVTs, in the basal plate). sFlt1-i13 transcripts were expressed primarily in EVTs in the basal plate and were significantly increased in preeclampsia (p<0.01, 2.53 fold). There were significant increases in cellularity, proliferation index (Ki-67-positive cells), and thickness of the sFlt1-expressing EVT cell layer in the basal plate in preeclampsia (p<0.01), suggesting that expansion of the sFlt1-i13-producing EVT layer in the basal plate in preeclampsia is the primary contributor to the increases in sFlt1 levels in preeclampsia. Because excess VEGF signaling has been implicated in the stimulation of placental sFlt1 production, we examined the effect of transient VEGF overexpression during early pregnancy in mice. VEGF was overexpressed in the placenta during days 6-9 of pregnancy using a Dox-inducible (TetOn3G), placenta-specific gene expression system developed in our laboratory. Zona-free blastocysts from transgenic animals expressing the Dox-responsive transcriptional activator TetOn3G were infected with a lentivirus expressing both VEGF and mCherry under the control of the TRE3G promoter and transferred into wild type pseudopregnant recipients (n=5). Transgenes were induced by Dox treatment in drinking water. VEGF overexpression led to a decrease in fetal size, an increase in placental size, and severe disruption of placental architecture, including dramatic expansion of the spongiotrophoblast layer and an increase in the size of trophoblast giant cells. Interestingly, these animals had significantly increased blood pressure and placental and serum levels of sFlt1 (49.7±8.6 vs 25.6±6.5 ng/ml) and proteinuria and focal glomerular endotheliosis in the kidney, all typical signs of preeclampsia in women. These results suggest that expansion of the sFlt1-i13-producing EVT layer in the basal plate in preeclampsia is the primary contributor to the increase in sFlt1 level in preeclampsia and that excess VEGF signaling during early placental development plays a role in the pathogenesis of preeclampsia through expansion of the sFlt1-producing EVT population in the basal plate.
收录类别	其他
语种	英语
内容类型	会议论文
源URL	[http://ir.siat.ac.cn:8080/handle/172644/10826]
专题	深圳先进技术研究院_医药所
作者单位	2016
推荐引用方式 GB/T 7714	BHOLA PRADHAN,XIUJUN FAN,SABITA DHAL,et al. VEGF Overexpression at Early Stages of Placental Development Leads to Expansion of the Spongiotrophoblast Layer andExcess sFlt1 Production – Relevance to Pathogenesis of Preeclampsia[C]. 见:Systems Biology of Reproduction SSR 49th Annual Meeting. 美国圣地亚哥.

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