Abstract
Fibrinogen-like 1 (FGL1) is involved in liver injury and liver regeneration, but its role in placenta and preeclampsia (PE) remains unclear. We assessed FGL1 expression in serum and placenta from L-NAME-induced PE-like mouse and in women with (n = 38) and without (n = 42) PE. For the mouse study, pregnant C57Bl/6 mouse (n = 6/group) were subcutaneously administered L-NAME with or without FGL1 once daily starting on days 7–14 of pregnancy and were sacrificed on gestational day (GD) 20. Maternal body weight, blood pressure, and urinary protein were assessed during GDs 8–20. The weight and length of the placenta and fetus were assessed. The placental structure was evaluated using hematoxylin staining. In the human study, the sera of the pregnant women during the late trimester were assessed with enzyme-linked immunosorbent assays (ELISAs). FGL1 expression in human trophoblast cell lines under L-NAME stimulation was measured using Western blotting and immunofluorescence staining. The detected FGL1 protein levels in serum and placenta were both significantly upregulated in patients and mouse with PE compared with those in the non-PE groups. FGL1 treatment decreased maternal hypertension and proteinuria, decreased fetal weight in mouse with PE, downregulated proinflammatory cytokine (interleukin-1b and interleukin-6) levels, and maintained the balance between antiangiogenic (fms-like tyrosine kinase-1) and proangiogenic (placental growth factor) substances in the placenta. L-NAME-upregulated FGL1 expression was inhibited following overexpression of FoxO3a. In summary, FoxO3a reduction is a potential pathophysiological mechanism leading to upregulated placental FGL1 expression that may play a pivotal role in preventing PE progression.
Highlights
Preeclampsia (PE) is one of the major issues in maternal-fetal medicine
Fibrinogen-like protein 1 (FGL1) gene and protein expression levels in the placentas from L-NAME-induced PE-like mouse were measured to determine the correlation between FGL1 and PE. qPCR, Western blotting, and immunofluorescence staining indicated that the FGL1 mRNA and protein expression levels in the placentas of the mouse with PE were significantly higher than those in the normal placentas
The results suggest that the placenta trophoblasts in decidua should be one of the sources of FGL-1 production in both mice and humans and FGL1 upregulation correlates with PE
Summary
Preeclampsia (PE) is one of the major issues in maternal-fetal medicine. According to the American College of Obstetricians and Gynecologists (ACOG) practice bulletin, the criteria for the diagnosis of PE are new-onset hypertension (systolic/diastolic pressure ≥140/90 mmHg) and proteinuria (a 24-h urine specimen with >300 mg protein) after gestational week 20 (Author Anonymous, 2019). PE occurs in approximately 4.6% of all pregnancies and causes substantial maternal and fetal morbidity and mortality worldwide (Abalos et al, 2013; Jeyabalan, 2013), and it affects approximately 1–2% of pregnancies in Taiwan (You et al, 2018) Several pathophysiological abnormalities, such as abnormal trophoblast differentiation and invasion, placental and endothelial dysfunction, immune maladaptation, and an exaggerated systemic inflammatory response, have been proposed to explain the pathogenesis of PE (Sibai et al, 2005; Sibai, 2008). PE can occur in the presence of trophoblast tissue with hydatidiform moles even in the absence of a fetus and abate with the delivery of the placenta (Lain and Roberts, 2002) This finding suggests that the placenta should be the root cause of PE, and analysis of the placenta should help to elucidate the pathophysiology of PE. Proteins structurally related to FGL1 (angiopoietins, fibrinogen, tenascins) have been implicated in multiple cellular processes, including angiogenesis, proliferation, apoptosis and extracellular matrix modulation (Procopio et al, 1999; Kim et al, 2000; Sahni and Francis, 2000; El-Karef et al, 2007), suggesting a potential role for placental FGL1 in these processes during PE progression
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