Decidual cells from preeclamptic pregnancies demonstrate inadequate decidualization and elevated sFlt1 production Public

Abstract

Uterine stromal cell decidualization of maternal tissue is essential for implantation of and local adaptation to the fetal allograft, as well as growth and maintenance of the placenta in healthy pregnancies. Maternal defects in decidualization have recently been suggested as a possible driver of preeclampsia, a common hypertensive disorder of pregnancy. Despite being responsible for a significant global burden of maternal and infant morbidity and mortality, the cause of the disease remains unknown and treatment is limited to prompt delivery of the placenta and fetus. Preeclamptic (PE) pregnancies demonstrate shallow implantation, inadequate spiral artery remodeling, and elevated levels of the anti-angiogenic protein, soluble fms-like tyrosine kinase-1 (sFlt1). To test whether decidual stromal cells (DSCs) isolated from PE placentas exhibit inadequate re-decidualization and increased expression of sFlt1, DSCs from 7 healthy (NT-DSCs) and 6 PE (PE-DSCs) placentas were treated for 8 days (D8) with cyclic adenosine monophosphate (cAMP) to induce decidualization and levels of decidualization markers prolactin (PRL), insulin-like growth factor binding protein 1 (IGFBP1), vascular endothelial growth factor (VEGF), and sFlt1 were measured at day 0 (D0), D8, and after reversal of treatment. NT-DSCs achieved statistically significant elevations in median PRL (25.72 IQR: [5.78 - 50.04], p=0.0008) and median IGFBP1 expression (and 92.09 [1.79 - 543.10], p=0.005). PE-DSCs increased PRL and IFGBP1 expression to 6.15 [2.30 - 10.73] (p=0.18) and 8.67 [1.64 - 376.10] (p=0.04). NT-DSCs reduced sFlt1 expression at D8 to 0.25 [0.17 - 0.49] (p=0.0021) compared to 0.31 [0.25 - 0.82] (p=0.087) in PE-DSCs. These results show that, when induced to decidualize, PE-DSCs fail to increase expression of decidualization markers to levels achieved by NT-DSCs. sFlt1 expression is higher in PE-DSCs during decidualization, suggesting inadequate suppression during the crucial implantation period. These defects at the maternal fetal interface may lead to the failed spiral artery modification, decreased placental invasion of the uterus, and elevated circulating sFlt1 levels seen in PE pathology. 

Table of Contents

Introduction………………………………………………………………………………..1

Background……………………………………………………………………………..…3

Methods………………………………………………………………………………..…..8

Results……………………………………………………………………………………14

Discussion………………………………………………………………………..………18

References………………………………………………………………………………..24

Tables…………………………………………………………………………………….27

           Table 1…………………………………………………………………………...27

           Table 2…………………………………………………………………………...28

Figures……………………………………………………………………………………29

Figure 1…………………………………………………………………………..29

Figure 2…………………………………………………………………………..30

Figure 3…………………………………………………………………………..31

Figure 4…………………………………………………………………………..32

About this Master's Thesis

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School	Laney Graduate School
Department	Clinical Research
Degree	M.S.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Human Development Health Sciences, Obstetrics and Gynecology
Mot-clé	hypertension preeclampsia VEGF pregnancy sFlt1 decidua
Committee Chair / Thesis Advisor	Henry Blumberg, Emory University
Committee Members	Amita Manatunga, Emory University Augustine Rajakumar, Emory University Thomas Ziegler, Emory University

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