Human Placental NADPH Oxidase Mediates sFlt-1 and PlGF Secretion in Early Pregnancy: Exploration of the TGF-β1/p38 MAPK Pathways

Abstract

Preeclampsia, a hypertensive disorder occurring during pregnancy, is characterized by excessive oxidative stress and trophoblast dysfunction with dysregulation of soluble Fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) production. Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase (Nox) is the major source of placental superoxide in early pregnancy and its activation with the subsequent formation of superoxide has been demonstrated for various agents including Transforming Growth Factor beta-1 (TGF-β1), a well-known p38 MAPK pathway activator. However, the bridge between Nox and sFlt-1 remains unknown. The purpose of this study was to explore the possible signaling pathway of TGF-β1/Nox/p38 induced sFlt-1 production in human chorionic villi (CV). Methods: Human chorionic villi from first trimester placenta (7–9 Gestational Weeks (GW)) were treated with TGF-β1 or preincubated with p38 inhibitor, SB203580. For NADPH oxidase inhibition, CV were treated with diphenyleneiodonium (DPI). The protein levels of phospho-p38, p38, phospho-Mothers Against Decapentaplegic homolog 2 (SMAD2), and SMAD2 were detected by Western blot. The secretion of sFlt-1 and PlGF by chorionic villi were measured with Electrochemiluminescence Immunologic Assays, and NADPH oxidase activity was monitored by lucigenin method. Results: We demonstrate for the first time that NADPH oxidase is involved in sFlt-1 and PlGF secretion in first trimester chorionic villi. Indeed, the inhibition of Nox by DPI decreases sFlt-1, and increases PlGF secretions. We also demonstrate the involvement of p38 MAPK in sFlt-1 secretion and Nox activation as blocking the p38 MAPK phosphorylation decreases both sFlt-1 secretion and superoxide production. Nevertheless, TGF-β1-mediated p38 activation do not seem to be involved in regulation of the first trimester placental angiogenic balance and no crosstalk was found between SMAD2 and p38 MAPK pathways. Conclusions: Thus, the placental NADPH oxidase play a major role in mediating the signal transduction cascade of sFlt-1 production. Furthermore, we highlight for the first time the involvement of p38 activation in first trimester placental Nox activity.

Hydrogen suppresses oxidative stress by inhibiting the p38 MAPK signaling pathway in preeclampsia

“…15 Among the potential cellular signaling pathways that could be impacted by ROS, the p38 MAPK pathway is a crucial candidate; it was shown to conduct signal transduction from the cell surface to the nucleus, [16][17][18] which would affect cellular survival, migration, proliferation, and differentiation. [19][20][21] Accumulated evidence indicates that the p38 MAPK pathway is one of the key signal pathways related to PE pathogenesis. 8,19,20 It has been demonstrated that nitration of phospho-p38 MAPK was higher in PE placentas.…”

“…[19][20][21] Accumulated evidence indicates that the p38 MAPK pathway is one of the key signal pathways related to PE pathogenesis. 8,19,20 It has been demonstrated that nitration of phospho-p38 MAPK was higher in PE placentas. 22 Reduced phospho-p38 MAPK concentration and p38 MAPK catalytic activity were also found in placentas from PE cases.…”

“…Similarly, we found that remarkable degeneration and excessive apoptosis in the placentas of the PE rat model and adverse pregnancy outcomes were associated with p38 MAPK signal activation. Furthermore, the activation of the p38 MAPK pathway in PE followed by placental nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 19 induced elevated sFlt-l and sEng expression in the maternal circulation. 8 This led to systemic vascular endothelial cell dysfunction 8 and the pathogenesis of PE.…”

Hydroxychloroquine reduces hypertension and soluble fms-like kinase-1 in a N ω-nitro-l-arginine methyl ester-induced preeclampsia rat model

“…The mitigation of NOX-induced oxidative stress in other cells also protects endothelial functions [61]. Given that placental NOX mediates sFlt-1 and placental growth factor secretion in first trimester chorionic villi [62], we could infer that the HCQ-mediated alleviation of preeclampsia and suppression of sFlt-1 and endothelin-1 signaling may involve NOX. Furthermore, HCQ and CQ function primarily by inhibiting lysosomal acidification, thus inhibiting autophagy in many cells [63].…”

Supraphysiological Role of Melatonin Over Vascular Dysfunction of Pregnancy, a New Therapeutic Agent?

“…Similarly, another member detected is the subunit CYBA gene elevated in preeclampsia ( Gomes et al, 2012 ; Trifonova et al, 2014 ), suggesting that the NADPH oxidase activity plays a critical role during the oxidative stress observed in the pregnancy. Moreover, elevated NADPH oxidase activity can modulate the production of sFlt-1 and PlGF, suggesting the critical role of this activity in developing preeclampsia ( Hernandez et al, 2021 ).…”