Epidermal growth factor rescues trophoblast apoptosis induced by reactive oxygen species |
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Authors: | Sarah J Moll Carolyn J P Jones Ian P Crocker Philip N Baker Alexander E P Heazell |
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Institution: | (1) Division of Human Development, St Mary’s Hospital, University of Manchester, Hathersage Road, Manchester, M13 0JH, UK |
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Abstract: | Pre-eclampsia and intrauterine growth restriction are associated with increased apoptosis of placental villous trophoblast.
This may result from placental hypoperfusion, leading to the generation of reactive oxygen species (ROS). Apoptosis can be
induced in villous trophoblast following exposure to oxidative stress. Epidermal growth factor (EGF) reduces trophoblast apoptosis
resulting from exposure to hypoxia. We hypothesised that exposure to hydrogen peroxide, a potent generator of ROS, would induce
apoptosis in term placental villous explants and that this could be reduced by treatment with EGF. Placental explants were
taken from normal term pregnancies and exposed to increasing doses of hydrogen peroxide (0–1,000 μM) or to a combination of
increasing doses of hydrogen peroxide and EGF (0–100 ng/ml) for either 6 or 48 h. Apoptosis was assessed by TUNEL, proliferation
by Ki-67 immunostaining, necrosis by lactate dehydrogenase activity and trophoblast differentiation by human chorionic gonadotrophin
(hCG) secretion in conditioned culture media. Immunoperoxidase staining was performed to identify phosphorylated-AKT (p-AKT)
and phosphorylated-PI3 kinase (p-PI3k). Exposure to 1,000 μM hydrogen peroxide for 48 h induced apoptosis in placental explants.
The increase in TUNEL positive nuclei predominantly localised to syncytiotrophoblast. The amount of apoptosis was reduced
to control levels by treatment with 10 and 100 ng/ml EGF. Proliferation of cytotrophoblasts within villous explants was significantly
reduced following exposure to 1,000 μM hydrogen peroxide, this was restored to control levels by simultaneous treatment with
10 or 100 ng/ml EGF. Neither exposure to hydrogen peroxide or EGF altered the amount of necrosis. There was increased immunostaining
for pPI3K following treatment with EGF. This study shows that apoptosis may be induced in villous trophoblast following exposure
to ROS, and demonstrates the anti-apoptotic effect of EGF in trophoblast, the maintenance of which is essential for normal
pregnancy. |
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Keywords: | Placenta Villous trophoblast Apoptosis Reactive oxygen species Epidermal growth factor |
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