ABSTRACT
sFLT1 (soluble VEGF [vascular endothelial growth factor] receptor-1) levels are increased in preeclampsia-a pathological condition of pregnancy. The mechanism of sFLT1 overexpression by gestational tissues, particularly the decidua, remains unknown. Mass spectrometry measurement of the active retinoid metabolite, all-trans retinoic acid (RA), showed significantly lower levels of RA in preeclamptic versus normotensive decidua. In this study, we investigated the involvement of RA in regulating decidual sFLT1 expression. When decidual stromal cells (DSCs) isolated from the decidua basalis of normotensive and preeclampsia placentas were treated with BMS493-a pan-RAR (RA nuclear receptor) antagonist-upregulation of sFLT1 expression was observed. Conversely, treatment with RA resulted in downregulation of sFLT1 in normotensive DSCs and preeclampsia DSCs. Unlike treatment with cAMP, which induces decidualization while downregulating sFLT1, RA treatment did not alter DSC expression of prolactin-a marker of decidualization-or FOXO1 (forkhead box protein 01)-a transcription factor required for prolactin upregulation. TFAP2A (transcription factor AP-2-alpha [activating enhancer-binding protein 2 alpha]), a different transcription factor was upregulated in normotensive DSCs but not in preeclampsia DSCs after RA treatment. Collectively, our data show that RA suppresses sFLT1 expression in DSCs independently of cellular decidualization. These findings suggest that reduced decidual RA levels may contribute to preeclampsia pathogenesis by allowing sFLT1 accumulation at the maternal-fetal interface.
Subject(s)
Decidua/metabolism , Gene Expression Regulation , Pre-Eclampsia/genetics , Stromal Cells/metabolism , Tretinoin/metabolism , Vascular Endothelial Growth Factor Receptor-1/genetics , Blotting, Western , Cell Differentiation , Cells, Cultured , Decidua/pathology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Pre-Eclampsia/blood , Pregnancy , RNA/genetics , Stromal Cells/pathology , Vascular Endothelial Growth Factor Receptor-1/biosynthesisABSTRACT
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 been suggested as a possible driver of preeclampsia. Preeclampsia (PE) pregnancies demonstrate shallow implantation, inadequate spiral artery remodeling, and elevated levels of the anti-angiogenic protein, sFlt1. To test whether stromal cells (DSCs) isolated from PE placentas exhibit inadequate re-decidualization and increased expression of sFlt1, DSCs from normotensive (NT-DSCs) and PE (PE-DSCs) placentas were treated for 8â¯days (D8) with cAMP to induce decidualization and levels of decidualization markers (PRL, IGFBP1, VEGF) and sFlt1 were measured at day 0 (D0), D8, and after reversal of treatment. NT-DSCs achieved statistically significant elevations in PRL and IFGBP1 expression (25.72 [5.78-50.04], pâ¯=â¯0.0008 and 92.09 [1.79-543.10], pâ¯=â¯0.005). PE-DSCs increased PRL and IFGBP1 expression to 6.15 [2.30-10.73] (pâ¯=â¯0.18) and 8.67 [1.64-376.10] (pâ¯=â¯0.04). NT-DSCs reduced sFlt1 expression at D8 to 0.25 [0.17-0.49] (pâ¯=â¯0.0021) compared to 0.31 [0.25-0.82] (pâ¯=â¯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.
