Abstract
Human chorionic gonadotropin (hCG) is a key autocrine/paracrine regulator of placental syncytiotrophoblast, the transport epithelium of the human placenta. Syncytiotrophoblast hCG secretion is modulated by the partial pressure of oxygen (pO2), reactive oxygen species (ROS) and potassium (K+) channels. Here we test the hypothesis that K+ channels mediate the effects of pO2 and ROS on hCG secretion. Placental villous explants from normal term pregnancies were cultured for 6 days at 6% (normoxia), 21% (hyperoxia) or 1% (hypoxia) pO2. On days 3–5, explants were treated with 5mM 4-aminopyridine (4-AP) or tetraethylammonium (TEA), blockers of pO2-sensitive voltage-gated K+ (KV) channels, or ROS (10–1000μM H2O2). hCG secretion and lactate dehydrogenase (LDH) release, a marker of necrosis, were determined daily. At day 6, hCG and LDH were measured in tissue lysate and 86Rb (K+) efflux assessed to estimate syncytiotrophoblast K+ permeability. hCG secretion and 86Rb efflux were significantly greater in explants maintained in 21% pO2 than normoxia. 4-AP/TEA inhibited hCG secretion to a greater extent at 21% than 6% and 1% pO2, and reduced 86Rb efflux at 21% but not 6% pO2. LDH release and tissue LDH/hCG were similar in 6%, 21% and 1% pO2 and unaffected by 4-AP/TEA. H2O2 stimulated 86Rb efflux and hCG secretion at normoxia but decreased 86Rb efflux, without affecting hCG secretion, at 21% pO2. 4-AP/TEA-sensitive K+ channels participate in pO2-sensitive hCG secretion from syncytiotrophoblast. ROS effects on both hCG secretion and 86Rb efflux are pO2-dependent but causal links between the two remain to be established.
Highlights
The endocrine and nutrient transport functions of the human placenta depend on appropriate maintenance of syncytiotrophoblast, a highly specialised multinucleate epithelial cell
This study confirms and extends previous observations that human chorionic gonadotrophin (hCG) secretion from term placental trophoblast is sensitive to pO2 [8, 18] and reactive oxygen species (ROS) [10]
In villous explants prepared from the same placenta, hCG secretion was higher in 21% pO2, and lower in 1% pO2, than 6% pO2 culture conditions
Summary
The endocrine and nutrient transport functions of the human placenta depend on appropriate maintenance of syncytiotrophoblast, a highly specialised multinucleate epithelial cell. PO2-Sensitive K+ Channels and hCG Secretion apoptosis and autophagy, to complete turnover [1, 2] In normal pregnancy these processes are highly coordinated but in pregnancies complicated by pre-eclampsia [3, 4], fetal growth restriction [4] and maternal obesity [5], an imbalance in cell turnover dysregulates syncytiotrophoblast renewal which compromises function and contributes to maternal and fetal mortality, and morbidity associated with these pregnancy complications. Using placental villous tissue from normal term pregnancy we compared the effect of KV channel blockers on hCG secretion and 86Rb efflux (a marker of K+ permeation through ion channels) from villous explants maintained at placental normoxia (6% pO2), with extreme hypoxia (1% pO2) and hyperoxia (21% pO2). We investigated the effect of H2O2, used to generate ROS, on hCG secretion and 86Rb efflux at the three different pO2
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