Objectives Preeclampsia (PE) is a complication of pregnancy and a leading cause of maternal and fetal morbidity and mortality. Despite being prevalent and highly morbid, there are no approved treatments to relieve PE signs and symptoms. Many studies have established that elevated levels of circulating anti-angiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) protein drives the maternal syndrome observed in PE, and reductions in sFlt-1 improved symptoms. We have previously reported that the bioflavonoid luteolin reduces sFlt-1 expression and the vasoconstrictor endothelin-1 (ET-1) in vitro and dilates uterine arteries ex vivo. Here, we set out to determine whether luteolin reduces mean arterial pressure (MAP), sFlt-1, and ET-1, and improves uterine artery resistance index (UARI) in the reduced uterine perfusion pressure (RUPP) rat model of PE. Study design On gestation day (GD) 14, animals were randomly separated into 4 groups: sham or RUPP treated with vehicle or luteolin (20 mg/kg/day). On GD19, MAP and UARI were measured, followed by blood and tissue collection. Main outcome measures Placental protein expression of sFlt-1 and HIF-1α (Western blot) and circulating levels of sFlt-1, placental growth factor (PlGF) and ET-1 were measured (ELISA). Results RUPP animals treated with luteolin demonstrated significant decreases in MAP, UARI, sFlt-1, and ET-1 compared to RUPP animals given a vehicle. There were no differences in sham animals treated with luteolin, and no adverse maternal or fetal outcomes were observed. Conclusions Luteolin effectively reduced blood pressure, improved uterine artery flow impedance, and reduced antiangiogenic markers in the RUPP model of PE without any observable adverse effects.

Two carboxylic ligands, HL1 {(Z)-4-(p-toluidino)-4-oxobut-2-enoic acid} and HL2 {(Z)-4-(4-fluorophenylamino)4-oxobut-2-enoic acid)} and their six novel triorganotin(IV) derivatives with the general formula R3SnL (wherein R = Me (1, 4), Bu (2, 5) and Ph (3, 6) were synthesized, characterized and evaluated for in vitro biological applications. Single crystal XRD and FT-IR data of the triorganotin(IV) complexes (1, 2 and 4) showed that they were polymeric in nature and that the tin(IV) ion was in a distorted trigonal bipyramidal environment. However, multinuclear NMR data (1H, 13C, 119Sn) suggested that the polymeric trigonal bipyramidal geometry remains intact for (Me)3SnL and (Bu)3SnL and (Ph)3SnL compounds in solution-state, whereas it switches tetrahedral geometry for (Bu)3SnL compound 5 which were analyzed for NMR in CDCl3, a non-coordinating solvent. A detailed analysis of their structural, electronic and physico-chemical properties, using DFT at B3LYP/LANL2DZ level, revealed results consistent with the single crystal data. Additionally, the study of their frontier molecular orbitals, Mulliken charges and molecular electrostatic potential surfaces provided valuable insights into their structure-property-relationship and physicochemical properties. In vitro studies examining antimicrobial activity, cytotoxicity, antioxidant properties, hemolysis, antileishmanial effects, and anticancer potential have demonstrated higher efficacy of complexes compared to their corresponding ligands.

In the field of human in vitro fertilization (IVF), selecting the best oocyte for freezing or embryo for transfer remains an important focus of clinical practice. Although several techniques are and have been used for this goal, results have generally not been favorable and/or are invasive such that damage to some embryos occurs, resulting in a reduced number of healthy births. Therefore, the search continues for non-invasive oocyte and embryo quality markers that signal the development of high-quality embryos. Multiple studies indicate the important positive effects of retinoic acid (RA) on oocyte maturation and function. We previously showed that a high follicular fluid (FF) RA concentration at the time of oocyte retrieval in IVF protocols was associated with oocytes, giving rise to the highest quality embryos, and that cumulus granulosa cells (CGCs) are the primary source of follicle RA synthesis. Data also demonstrated that connexin-43 (Cx43), the main connexin that forms gap junctions in CGCs, is regulated by RA and that RA induces a rapid increase in gap junction communication. Here, we hypothesize that CGC RA plays a causal role in oocyte competency through its action on Cx43 and, as such, may serve as a biomarker of oocyte competence. Multiple studies have demonstrated the requirement for Cx43 in CGCs for the normal progression of folliculogenesis, and that the increased expression of this connexin is linked to the improved developmental competence of the oocyte. The data have shown that RA can up-regulate gap junction intercellular communication (GJIC) in the cumulus–oocyte complex via a non-genomic mechanism that results in the dephosphorylation of Cx43 and enhanced GJIC. Recognizing the positive role played by gap junctions in CGCs in oocyte development and the regulation of Cx43 by RA, the findings have highlighted the possibility that CGC RA levels may serve as a non-invasive indicator for selecting high-quality oocytes for IVF procedures. In addition, the data suggest that the manipulation of Cx43 with retinoid compounds could provide new pharmacological approaches to improve IVF outcomes in cases of failed implantation, recurrent miscarriage, or in certain diseases that are characterized by reduced fecundity, such as endometriosis.

Preeclampsia (PE) is a pregnancy disease characterized by maternal hypertension and vascular dysfunction. PE is believed to originate from the ischemic/hypoxic placenta that activate local HIF-1α-mediated release of anti-angiogenic sFlt-1 and release of inflammatory cytokines, such as TNF-α. Signaling from both sFlt-1 and TNF-α-induced NF-κB activation result in upregulation of the potent vasoconstrictor ET-1. Antagonism of ET-1 signaling has been shown to relieve symptoms in animal models of PE, but these treatments are contraindicated in pregnancy. Luteolin is a naturally occurring bioflavonoid that has been studied for its use as an anti-inflammatory and anti-hypertensive agent but has never been studied in PE. In this in vitro study, we tested the hypothesis that luteolin may attenuate pathways involved in vascular dysfunction by attenuating HIF-1α increase (via upstream PI3K and ERK) as well as TNF-α-induced NF-κB activation. To study HIF-1α inhibition by luteolin, placental explants from normotensive patients were treated under normoxic (20%) and hypoxic (2%) conditions with luteolin (10μM) for 72 hours, in the presence and absence of relevant inhibitors; PI3K inhibitor (LY294002, 50μM) and ERK inhibitor (U0126, 20μM). Western blots were used to measure HIF-1α protein changes. HUVEC cells were stimulated by TNF-α in the presence or absence of luteolin to determine NF-κB nuclearization by immunofluorescence.Hypoxic incubations significantly increased HIF-1α compared to normoxia (1.44 + 0.43 vs 0.55 + 0.21 arbitrary units (AU); p<0.001). Although HIF-1α expression remained unchanged regardless of treatment in normoxic samples, hypoxic samples treated with luteolin had a significant reduction of HIF-1α expression (1.44 + 0.43 vs 0.51 + 0.09 AU; p<0.01). Similarly, HIF-1α expression was reduced by PI3K inhibitor treatment in hypoxia (1.44 + 0.43 vs 0.56 + 0.18 AU; p<0.01) and ERK 1/2 inhibitor (1.44 + 0.43 vs 0.66 + 0.24 AU; p<0.05). The combination of luteolin and inhibitors did not result in an additive effect. NF-κB nuclearization increased significantly after stimulation with TNF-α (0.38 + 0.13 vs 1.07 + 0.45 AU; p<0.01), which was ameliorated by luteolin to 0.51 + 0.18 AU (p<0.05).Maternal vascular dysfunction is a final common pathway in the pathogenesis of PE, stimulated by upregulation of ET-1. Signaling by ET-1 is promoted by upregulation of HIF-1α-induced sFlt-1 and TNF-α activation of NF-κB. Luteolin, based on our data, is capable of targeting these pathways of ET-1 upregulation and has the potential to serve as a therapeutic for PE. This work was supported by NIH 1R56HL157579-01. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Preeclampsia (PE) is a serious hypertensive complication of pregnancy and is a leading cause of maternal death and major contributor to maternal and perinatal morbidity, including establishment of long-term complications. The continued prevalence of PE stresses the need for identification of novel treatments which can target prohypertensive factors implicated in the disease pathophysiology, such as soluble fms-like tyrosine kinase 1 (sFlt-1). We set out to identify novel compounds to reduce placental sFlt-1 and determine whether this occurs via hypoxia-inducible factor (HIF)-1α inhibition. We utilized a commercially available library of natural compounds to assess their ability to reduce sFlt-1 release from primary human placental cytotrophoblast cells (CTBs). Human placental explants from normotensive (NT) and preeclamptic (PE) pregnancies were treated with varying concentrations of luteolin. Protein and mRNA expression of sFlt-1 and upstream mediators were evaluated using ELISA, western blot, and real-time PCR. Of the natural compounds examined, luteolin showed the most potent inhibition of sFlt-1 release, with >95% reduction compared to vehicle-treated. Luteolin significantly inhibited sFlt-1 in cultured placental explants compared to vehicle-treated in a dose- and time-dependent manner. Additionally, significant decreases in HIF-1α expression were observed in luteolin-treated explants, suggesting a mechanism for sFlt-1 downregulation. The ability of luteolin to inhibit HIF-1α may be mediated through the Akt pathway, as inhibitors to Akt and its upstream regulator phosphatidylinositol-3 kinase (PI3K) resulted in significant HIF-1α reduction. Luteolin reduces anti-angiogenic sFlt-1 through inhibition of HIF-1α, making it a novel candidate for the treatment of PE.

INTRODUCTION:Preeclampsia (PE) is a serious hypertensive pregnancy disorder and a leading cause of maternal and perinatal morbidity and mortality. Despite the prevalence and complications, there are no approved therapeutics to relieve PE symptoms. Inflammation, oxidative stress, and angiogenic imbalance have been shown to contribute to the PE pathophysiology, though there is a lack of understanding in how best to target these pathways in PE. We recently demonstrated that the bioflavonoid luteolin is a potent inhibitor of the anti-angiogenic and pro-hypertensive soluble fms-like tyrosine kinase 1 (sFlt-1), and here we aimed to determine if luteolin was also capable of reducing inflammation and oxidative stress pathways. METHODS:Tumor necrosis factor (TNF)-α, which is upregulated in PE, was utilized to stimulate these pathways in human placental explants and endothelial cells. Endothelin-1 (ET-1) and interleukin (IL)-6 in the media from explants and cells were measured via ELISA, and NF-κB localization and reactive oxygen species were detected via fluorescence microscopy. RESULTS:Pretreatment with luteolin demonstrated significant reductions in NF-κB activation, reactive oxygen species, superoxide, and IL-6 and ET-1 expression in endothelial cells. We also saw a significant reduction in phosphorylation of NF-κB in human placental explants. DISCUSSION:These data demonstrate that luteolin inhibits pathways implicated in the development of PE and should be explored further for its potential as a PE therapeutic.

Introduction: Human placenta is often considered a controlled-tumour because of shared properties such as invasion and angiogenesis. We assessed the status of a few selected tumour-associated factors (TAFs) in late onset pre-eclamptic (PE) and normotensive (NT) placentae, to understand their involvement in trophoblast invasion. These molecules include aldehyde dehydrogenase (ALDH3A1), aurora kinases (AURK-A/C), platelet derived growth factor receptor-alpha (PDGFR alpha), jagged-1 (JAG1) and twist related protein-1 (TWIST1). Methods: The expression of TAF was compared in 13 NT and 11 PE (late onset) placentae using immunoblotting/ immunohistochemistry. We then used a novel spheroidal cell model developed from transformed human first trimester trophoblast cell lines HTR8/SVneo and TEV-1 to determine the expression and localization of these six factors during invasion. We also compared the expression of these TAFs during migration and invasion. Results: Our results suggest that expressions of ALDH3A1, AURK-A, PDGFR alpha, and TWIST1 are significantly upregulated in PE placentae (p < 0.05) when compared to NT placentae, whereas AURK-C and JAG1 are downregulated (p < 0.05). The protein expression pattern of all the six factors were found to be similar in spheroids in comparison to their parental counterparts. The invasive potential of the spheroids was also enhanced when compared with the parental cells. Discussion: Collectively, data from our present study suggests that these TAFs are involved in placental invasion and their altered expressions may be regarded as a compensatory mechanism against reduced invasion.

Six new triorganotin(IV) carboxylates with the general formula (R or Ar) 3 SnL [where R or Ar = Me ( 1 , 4 ), Bu ( 2 , 5 ) and Ph ( 3 , 6 ) and L = (Z)-4-( p -toluidino)-4-oxobut-2-enoate (for complexes 1-3 ) and (Z)-4-(4-fluorophenylamino)-4-oxobut-2-enoate (for complexes 4- 6 )] are report herein. Solid state characterization [X-ray diffraction structural ( 1 , 2 and 4 ) analysis and FT-IR ( 1-6 )] unveiled the polymeric nature of the triorganotins imposed by a bridging coordination of a carboxylate ligand. Each Sn atom is five-coordinated with approximately trigonal bipyramidal geometry. However, in case of Me 3 SnL and Bu 3 SnL complexes, trigonal bipyramidal configuration switches to tetrahedral in solution, as evident by 1 H, 13 C and 119 Sn NMR. The structural, electronic and physicochemical properties of the compounds are explained using density functional theory at B3LYP/LANL2DZ level. The frontier molecular orbitals, Mulliken charge analyses and molecular electrostatic potential surfaces have been calculated to analyse the structure-property relationships (SARs) and physicochemical properties of complexes. Anticancer and noncancerous cells activities exposed the more active nature of complexes than the corresponding ligands. Furthermore, complexes have good antileshmanial and antioxidant activities.

Preeclampsia (PE) is a prevalent pregnancy disorder that leads to high maternal and fetal morbidity and mortality. While defective vascular development and angiogenesis in placenta are known as crucial pathological findings, its pathophysiological mechanism remains elusive. To better understand the effects of PE on angio-vasculogenesis and inflammatory networks in the fetus and to identify their biological signatures, we investigated the quantitative and functional characteristics of cord blood-derived mononuclear cells (CB-MNCs) and CD31-positive MNCs. Flow cytometry analysis demonstrated that the CB-MNCs from the severe PE group had significantly decreased number of cells expressing CD3, CD11b, CD14, CD19, KDR, and CD31 compared with the normal group. Quantitative real time PCR (qRT-PCR) shows down-regulation of the major angiogenic factor VEGFA in MNCs and CD31+ MNCs in severe PE. The major inflammatory cytokines IL1 was highly upregulated in CD31+ CB-MNCs in the severe PE patients. Mild PE patients, however, did not display any significant difference in expression of all measured angiogenic genes and most inflammatory genes. These findings show distinct angiogenic and inflammatory signatures from severe PE, and they may play a significant role in the pathogenesis of vascular defects in placenta of severe PE.

Preeclampsia (PE) yields a spectrum of phenotypic expression, leading to varying degrees of hypertension, maternal renal dysfunction and placental insufficiency with resultant maternal and neonatal morbidity. Increased sFLT1 expression contributing to angiogenic factor imbalance, placental hypoxia, failed immune adaptation to the fetus and defective decidualization are among the commonly proposed theories of PE pathogenesis. Recently researchers have focused their attention on the events that occur at the maternal fetal interface as potential contributors to PE pathogenesis. Decidual stromal cells (DSC) isolated from preeclamptic women show diminished ability to decidualize upon stimulation and reduced capacity to downregulate sFlt-1 levels. In this study, we sought to gain insight into the molecular mechanism(s) involved in the aberrant decidualization capacity of PE DSC. Our findings using qRT-PCR show that PE DSCs have 6-fold higher basal levels of transcription factor AP2A (TFAP2A) RNA compared to women without PE and that expression of TFAP2A increases during decidualization but only in DSCs of normotensive (NT) women. Silencing of TFAP2A using Trilencer siRNA upregulated sFLT1 expression only in NT-DSCs but suppressed the expression of decidualization markers PRL, IGFBP1 and their regulator FOXO1 in cells from both groups. Collectively, our observations suggest that TFAP2A acts as a repressor of sFLT1 and plays a necessary role in decidualization possibly through interacting with another factor that is aberrantly expressed in PE DSCs.

Decidual stromal cells (DSC) from women with preeclampsia (PE) show defective decidualization upon in vitro treatment with cAMP. Decidualization is associated with a multitude of gene expression changes and is a prerequisite for embryo implantation. We reason that the process of decidualization involves a cascade of changes in transcriptional regulators. Our prior studies have found defective decidualization of PE-DSCs as reflected by low prolactin (PRL) levels and other decidualization markers. Transcription factor array analysis identified inhibitor of DNA binding (ID1) and FOXO1 as top differentially expressed genes during decidualization. Unlike ID1, FOXO1 involvement in decidualization has been established. We hypothesized that ID1 plays a major role in regulating stromal cell decidualization. Our data shows basal ID1 mRNA expression is significantly higher in PE DSCs. Cyclic AMP-mediated decidualization significantly upregulates ID1 mRNA expression in DSCs and siRNA-mediated knockdown of ID1 significantly interferes with decidualization as shown by a reduction in PRL and FOXO1 expression, and morphologic criteria. Thus ID1 may serve as a master regulator of stromal cell differentiation and defects in ID1 expression may affect decidualization as seen in PE-DSCs.

Fine-tuning of the endometrium during the evanescent 'window of implantation' relies upon an array of diverse and redundant signaling molecules, particularly the ovarian steroids E2 and P4, but also growth factors, eicosanoids, and vitamins including the vitamin A compounds (retinoids). Pregnancy complications such as preeclampsia (PE) can result from aberrations in the production or function of these molecules that arise during this critical period of decidual development. Such aberrations may be reflected by incomplete decidualization, reduced spiral artery modification, and/or loss of immune tolerance to the developing fetus. Our understanding of the role of the active retinoid metabolite all-trans retinoic acid (RA) in maintaining immune balance in certain tissues, along with data describing its role in decidualization, present a compelling argument that aberrant RA signaling in the decidua can play a significant role in the etiology of PE. Recent findings that decidualization and expression of the anti-angiogenic gene product, 'soluble fms-like tyrosine kinase-1' (sFLT1) are negatively correlated and that sFLT1 expression is directly inhibited by RA, provide additional evidence of the critical role of this retinoid in regulating early vascular development in the decidua. This review provides insight into the production and function of RA in the decidua and how modifications in its metabolism and signaling might lead to certain pregnancy disorders such as PE.

Four new triorganotin(IV) amide based carboxylates of general formula R3SnL1 and R3SnL2, where R = Me(1,3) and n-butyl (2,4), and L-1 = (Z) 4 (p methoxyphenylamino)-4-oxo-2-butenoic acid (HL1) L-2 = (Z)-4-(3,5-bis (trifluoromethyl)phenylamino)-4-oxo-2-butenoic acid (HL2) have been synthesized by refluxing methanolic solution of organtin(IV) chloride and ligand (1:1 M ratio). The synthesized compounds were characterized by FT-IR, elemental analysis, NMR (H-1, C-13, Sn-119 & F-19) and single crystal X-ray crystallography. The ligands co-ordinate to fin atom through oxygens (carboxylate and amide) showing distorted trigonal bipyramidal geometry with polymeric bridging behavior in solid state. However, the geometry is switched over from trigonal bipyramidal to tetrahedral upon dissolution as confirmed by multinuclear (H-1, C-13, F-19 and Sn-119) NMR. The prepared ligands and compounds 1-4 were screened for antimicrobial, antioxidant, cytotoxicity, hemolysis, antileishmanial and anticancer and noncancerous activities. The results showed significant antimicrobial activities, antioxidant, good cytotoxic LD50 values, percent hemolytic values, antileishmanial and anti-cancer activities. Compound 2 and 4 were found the most active antileishmanial and anticancer agent, respectively.

In situ production and metabolism of all-trans retinoic acid (RA) in decidual tissue are critically important for endometrial stromal differentiation, embryo implantation, and healthy placentation. However, the cellular source(s) of RA in this tissue has yet to be determined. To identify the primary RA-producing cells in human term decidua, we isolated cells from decidua basalis of delivered placenta and quantified cellular retinal dehydrogenase (RALDH) activity, a major biosynthetic enzyme whose activity determines the synthesis of RA from retinol, using an Aldefluor assay and flow cytometry. RA production in decidual tissue and sorted cell subpopulations was evaluated by liquid chromatography-tandem mass spectrometry. CD14(+) cells (macrophages/monocytes) showed > 4-fold higher RALDH activity than stromal cells (CD10(+)), T cells (CD3(+)), or non-T lymphocytes (CD3-negative). CD11c(+) cells that did not co-express CD14 showed about one-third the RALDH activity of their CD14 co-expressing counterparts. The highest RALDH activity was found in "alternatively activated" M2 macrophages delineated by the simultaneous expression of CD14 and CD163. The greater RA synthesizing capacity of M2 versus CD14(+)CD163-ve (M1) cells was confirmed by direct quantitation of RA biosynthesis from retinol. RA levels in whole decidua were correlated with M2 cell density but not with stromal cell (CD10(+)) number, the major cell type comprising the decidua. These results identified M2 monocyte/macrophages as the primary source of RA in human term decidua. This finding may have implications for certain pregnancy complications that are known to be associated with reduced numbers of decidual M2 cells.

CONTEXT Implantation is a reproductive bottleneck in women, regulated by fluctuations in ovarian steroid hormone concentrations. However, other nuclear receptor ligands are modifiers of endometrial differentiation leading to successful pregnancy. In the current study we analyzed the effects of PPARβ/δ activation on established cellular biomarkers of human endometrial differentiation (decidualization). OBJECTIVE To test the effects of PPARβ/δ ligation on human endometrial cell differentiation. DESIGN Isolated primary human endometrial stromal cells (ESC) were treated with synthetic (GW0742) or natural (all trans-retinoic acid, RA) ligands of PPARβ/δ, and also with receptor antagonists (GSK0660, PT-S58 and ST247) in the absence or presence of decidualizing hormones (10 nM estradiol, 10 nM progesterone and 0.5 mM dibutyryl cAMP). In some cases interleukin (IL)-1β was used as an inflammatory stimulus. Time course and dose-response relationships were evaluated to determine effects on panels of well characterized in vitro biomarkers of decidualization. RESULTS PPARβ/δ, along with ERα and PR-A and -B were expressed in human endometrial tissue and isolated ESC. GW0742 treatment enhanced hormone-mediated ESC decidualization in vitro as manifested by upregulation of prolactin, IGFBP-1, IL-11 and VEGF secretion and also increased expression of ERα, PR-A and -B and Cx43. RA treatment also increased VEGF, ERα, PR-A and -B and an active, non-phosphorylated isoform of Cx43. IL-1β and PPARβ/δ antagonists inhibited biomarkers of endometrial differentiation. CONCLUSION Ligands that activate PPARβ/δ augment the in vitro expression of biomarkers of ESC decidualization. By contrast, PPARβ/δ antagonists impaired decidualization markers. Drugs activating these receptors may have therapeutic benefits for embryonic implantation.

Preeclamptic decidual stromal cells (DSCs) exhibit defective decidualization. We have found Transcription Factor AP2A (TFAP2A) expression is significantly upregulated during cAMP-mediated decidualization of DSCs in normal pregnancy, but not in DSCs of pregnancies affected by preeclampsia (PE). The objective of the study is to delineate the association of the expression of TFAP2A to defective decidualization. Human decidual stromal cells were obtained from decidua basalis of normal and PE placentas at term (n=5 in each group). To determine its role in decidualization, TFAP2A was knocked down in DSCs using siRNA (1.0 nM, Origene) and the cells further incubated in the presence and absence of cAMP, a known inducer of decidualization. Negative controls to check specificity (random RNA) and fluorescent tagged siRNA to validate transfection efficiency were employed. SYBR green-based qPCR was used to determine gene expression levels of decidualization markers PRL, IGFBP1 and FOXO1, a known regulator of PRL and IGFBP1. Immunohistochemistry (IHC) was performed to determine FOXO1 protein levels. Data was analyzed using GraphPad Prism. Treatment effects between groups was analyzed by Kruskal-Wallis test. Comparison between two samples was performed by Mann-Whitney U test. p< 0.05 was considered significant. Transfection efficiency of siRNA into DSC was 80-90%. siRNA-mediated downregulation of TFAP2A significantly reduced expression of decidualization markers PRL and IGFBP1 (80%, p< 0.05). The level of regulator FOXO1 was also significantly reduced (50%, p< 0.05). IHC showed significantly altered FOXO1 protein levels similar to RNA levels. There was no significant effect on the markers by the negative control siRNA. Our studies show upregulation of TFAP2A is involved in the decidualization process. This observation, along with our prior report of defective decidualization of PE-DSCs and reduced upregulation of TFAP2A, suggest TFAP2A may be a major contributor to preeclampsia pathogenesis originating at the maternal fetal interface during early stages of placental development.

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.