Onset of Maternal Arterial Blood Flow and Placental Oxidative Stress

Abstract

The aim was to measure changes in the oxygen tension within the human placenta associated with onset of the maternal arterial circulation at the end of the first trimester of pregnancy, and the impact on placental tissues. Using a multiparameter probe we established that the oxygen tension rises steeply from <20 mmHg at 8 weeks of gestation to >50 mmHg at 12 weeks. This rise coincides with morphological changes in the uterine arteries that allow free flow of maternal blood into the placenta, and is associated with increases in the mRNA concentrations and activities of the antioxidant enzymes catalase, glutathione peroxidase, and manganese and copper/zinc superoxide dismutase within placental tissues. Between 8 to 9 weeks there is a sharp peak of expression of the inducible form of heat shock protein 70, formation of nitrotyrosine residues, and derangement of the mitochondrial cristae within the syncytiotrophoblast. We conclude that a burst of oxidative stress occurs in the normal placenta as the maternal circulation is established. We speculate that this may serve a physiological role in stimulating normal placental differentiation, but may also be a factor in the pathogenesis of pre-eclampsia and early pregnancy failure if antioxidant defenses are depleted.

Role of Hypoxia-Inducible Transcription Factors 1α and 2α in the Regulation of Plasminogen Activator Inhibitor-1 Expression in a Human Trophoblast Cell Line

“…Conversely, PAI-2 levels were not significantly affected by hypoxic treatment. Cells were maintained at an oxygen concentration of 1−3% oxygen, a level similar to that which the placenta is exposed to before 10 weeks of pregnancy [32]. These results are consistent with previous studies demonstrating hypoxic induction of PAI-1 expression in trophoblasts and other cell types, and the demonstration of a HRE in the PAI-1 promoter [21][22][23].…”

“…Previous studies have used siRNAs to down-regulate HIF-1α and/or HIF-2α expression in cancer cell lines [26,28], but not in trophoblasts or trophoblast cell lines, and their effect on PAI levels was not examined. This study is relevant to PAI regulation in early pregnancy when the placenta is exposed to relatively hypoxic conditions (2−3% O 2 ) in the first 10 weeks of gestation [32], as well as to pregnancies complicated by PE which is associated with prolonged hypoxia and aberrant PAI-1 expression at the maternal-placental interface [1,4,14,15].…”

Pro- and antiinflammatory cytokines in threatened miscarriages

“…7 We previously have shown that the underlying uteroplacental circulation in the center of the primitive placenta is plugged, whereas in periphery the mouth of the spiral arteries are never plugged by the trophoblastic shell, which allows limited maternal blood flow to enter the marginal zone of placenta from 8-9 weeks of gestation. 8 This leads to higher local O 2 concentration at a stage of pregnancy when the trophoblast possesses low concentrations of the main antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase. 7 Focal trophoblastic oxidative damage and progressive villous degeneration trigger the formation of fetal membranes, which remodels the uteroplacental interface.…”

“…If the hematoma expands to the rest of the placental mass, it will induce complete miscarriage within a week of the first symptoms. 8 If bleeding is limited or happens close to the internal cervical os and is evacuated, the pregnancy may continue; however, this can lead to a chronic inflammatory reaction within the decidua and membranes. 7,8 Within this context, TM is associated with a higher incidence of preterm labor, prelabor rupture of membranes, placental abruption, fetal growth restriction, and low birthweight.…”

“…8 If bleeding is limited or happens close to the internal cervical os and is evacuated, the pregnancy may continue; however, this can lead to a chronic inflammatory reaction within the decidua and membranes. 7,8 Within this context, TM is associated with a higher incidence of preterm labor, prelabor rupture of membranes, placental abruption, fetal growth restriction, and low birthweight. 2,[9][10][11][12][13][14][15][16][17][18] A strong association exists between maternal T helper-1 (Th1)-type immunity and pregnancy loss, whereas a shift towards Th2-type cytokine response has been observed in successful pregnancy.…”