tretinoin and Pre-Eclampsia

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.

Topics: Decidua; Female; Humans; Pre-Eclampsia; Pregnancy; Tretinoin; Vascular Endothelial Growth Factor Receptor-1

Acute promyelocytic leukemia (APL) manifesting during pregnancy is a very rare but highly challenging gestational complication in part due to its associated profound coagulopathy. We present the case of a 23-year-old Gravida 3 Para 2002 woman admitted to our hospital at 26 weeks of gestation for severe pre-eclampsia with documentation of intrauterine fetal demise (IUFD), thrombocytopenia, and placental abruption. A peripheral blood smear revealed promyelocytes with azure granules, highly concerning for APL. Additional peripheral blood studies confirmed APL. Placental examination also revealed circulating blasts in decidual vessels and scattered blast entrapment in diffuse perivillous fibrinoid deposits, but none in the chorionic villi. Treatment for APL was initiated immediately and she is in complete molecular remission. Our case underscores the importance of close collaboration among obstetric, hematology, and pathology teams in the care of patients with pre-eclampsia, thrombocytopenia, and postpartum coagulopathy. We also describe five additional cases of gestations complicated by hematologic malignancies identified upon a 10-year institutional retrospective review.

Topics: Abruptio Placentae; Antineoplastic Agents; Disseminated Intravascular Coagulation; Female; Fetal Death; Humans; Leukemia, Promyelocytic, Acute; Postpartum Period; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Neoplastic; Retrospective Studies; Treatment Outcome; Tretinoin; Young Adult

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.

Topics: Blotting, Western; Cell Differentiation; Cells, Cultured; Decidua; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression Regulation; Humans; Pre-Eclampsia; Pregnancy; RNA; Stromal Cells; Tretinoin; Vascular Endothelial Growth Factor Receptor-1

Cytotrophoblast (CT) cell fusion into a syncytiotrophoblast is obligatory for placentation and mediated by the human endogenous retrovirus (HERV)-W envelope gene Syncytin-1. Abnormal placentation is associated with preeclampsia (PE), HELLP and intrauterine growth restriction (IUGR). In placentogenesis, the MAP-kinase p38α regulates PPARγ/RXRα signaling and target genes, like leptin, resistin, ABCG2, and hCG. The aim of this study was to analyze PPARγ/RXRα signaling and target gene regulation using primary CT cultures, the trophoblastic cell line BeWo and placental tissues from patients with normal and abnormal placentation. CT from four different human control placentae and BeWo cells demonstrated that Syncytin-1, other signaling members and CT cell fusions were regulated with PPARγ/RXRα activators troglitazone and 9-cis retinoic acid, via protein kinase A and p38α inhibition. Significant discordant regulations between CTs and BeWo were found. Two PPARγ/RXRα-response-elements from upstream regulatory elements and the 5'LTR of HERV-W were confirmed with DNA-protein binding assays using nuclear extracts and recombinant PPARγ/RXRα proteins. These promoter elements were validated with luciferase assays in the presence of PPARγ/RXRα modulators. Furthermore, troglitazone or 9-cis retinoic acid treatment of siRNA-PPARγ and siRNA-RXRα transfected BeWo cells proved the requirement of these proteins for Syncytin-1 regulation. Thirty primary abnormal placentae from PE, HELLP and IUGR patients compared to 10 controls showed significant deregulation of leptin RNA and protein, p38α, phospho-p38α, PPARγ, ABCG2, INSL4 and Syncytin-1. Our study characterized PPARγ/RXRα signaling in human CT and cell fusions identifying Syncytin-1 as a new target gene. Based on these results, a disturbed PPARγ/RXRα pathway could contribute to pathological human pregnancies.

Topics: Alitretinoin; Cell Fusion; Cell Line; Chromans; Cyclic AMP-Dependent Protein Kinases; Endogenous Retroviruses; Female; Fetal Growth Retardation; Gene Expression Regulation; Gene Products, env; HELLP Syndrome; Humans; Mitogen-Activated Protein Kinase 14; Placenta; Placentation; PPAR gamma; Pre-Eclampsia; Pregnancy; Pregnancy Proteins; Response Elements; Retinoid X Receptor alpha; RNA Interference; RNA, Small Interfering; Signal Transduction; Thiazolidinediones; Tretinoin; Troglitazone; Trophoblasts