Abstract
First-trimester placenta (<10 gestational weeks (GW)) develops in a low oxygen environment (≈2%). Early oxygen exposure can cause oxidative damage leading to pregnancy disorders. The aim of this work was to determine the major sources of placental superoxide during early pregnancy - more specifically before 10 GW - and to study redox adaptation to increased oxygen pressure after 12 GW. Our results show that NADPH oxidase (Nox) is the main source of superoxide in first-trimester chorionic villi. Its activity is higher before 10 GW and concomitant with the location on the syncytiotrophoblast apical pole of p47phox, the Nox organizer subunit. After the increase in pO2 pressure (12–14 GW), the activities of the antioxidant enzymes SOD1, catalase and GPX1 are increased. The redox-sensitive MAPK pathways show increased phosphorylated-p38 expression, but no variation in the phosphorylation of stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) during first trimester, suggesting a physiological redox adaptation, whilst ERK1/2 phosphorylation is higher after 12 GW. Nox is the major superoxide source in early pregnancy (<10 GW). Increased superoxide production at 7–9 GW is associated with p38 MAPK pathway activation, suggesting that it is involved in physiological placental function and healthy early development of the placenta, through MAPK pathways.
Highlights
During pregnancy, the chorionic villus, which represents the essential structural and functional component of the human placenta, undergoes drastic changes
NADPH oxidase (Nox) has been described in several cell types, especially in the neutrophils where production of superoxide anion is involved in phagocytosis, but few studies have explored the isoform of Nox in human placenta
All placentas were obtained from singleton pregnancies after voluntary abortion; none were from an assisted reproductive technology (ART) procedure
Summary
The chorionic villus, which represents the essential structural and functional component of the human placenta, undergoes drastic changes It first develops in a low-oxygen environment throughout the first trimester[1] due to the obstruction of uterine arteries by the invasive trophoblastic cells; the oxygen pressure is about 20 mmHg in the intervillous space. As redox-sensitive pathways, MAPK may be activated by Nox: in endothelial cells, Nox[1], Nox[2] and Nox[4] isoforms are involved in inflammatory response and cytokine expression, triggered by angiotensin II treatment, through different MAPK pathways activation (p38, ERK 1⁄2 and SAPK/JNK)[15] In placenta, these pathways seems to be involved in trophoblast differentiation and proliferation[16,17,18,19]. We measured superoxide production with or without specific inhibitors of superoxide producers (Nox, mitochondrial respiratory chain and endothelial nitric oxide synthase (eNOS)) and studied the activity and location of the main antioxidant enzymes before and after the critical low-oxygen (7–9 GW) to high-oxygen (12–14 GW) switch, as well as the phosphorylated expression of MAPK proteins, which has never been done before
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