Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non-native women at high altitude

Pregnancy at high altitude is associated with a reduction in birth weight of similar to 100 g/1000 m of ascent. The underlying mechanisms are unclear but may involve alteration in energy-demanding activities, such as protein synthesis. To test this hypothesis, both in vivo and in vitro approaches were used. Placental tissues from pregnant women residing at 3100 m were studied, and placental cells were incubated under hypoxia. In the 3100-m placentas, we observed dilation of endoplasmic reticulum (ER) cisternae, increased phosphorylation of eukaryotic initiation factor 2 subunit alpha (P-eIF2 alpha), reduced AKT phosphorylation, and reduced P-4E-BP1 but increased 4E-BP1 protein compared to sea level controls. These findings suggest the presence of ER stress and protein synthesis inhibition. Hypoxia (1% O-2) reduced proliferation of trophoblast-like JEG-3 cells, BeWo cells, and placental fibroblasts by similar to 40, similar to 60, and similar to 18%, respectively. Sublethal dosage of salubrinal, an eIF2 alpha phosphatase inhibitor, increased P-eIF2 alpha and reduced BeWo cell and placental fibroblast proliferation by similar to 50%. Administration of the PI-3K inhibitor LY294002 also reduced JEG-3 proliferation. Our results demonstrate that exposure to chronic hypobaric hypoxia causes mild placental ER stress, which, in turn, modulates protein synthesis and slows proliferation. These effects may account for the reduced placental villous volume, and contribute to the low birth weight that typifies high-altitude populations.-Yung, H. W., Cox, M., Tissot van Patot, M., Burton, G. J. Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non-native women at high altitude. FASEB J. 26, 1970-1981 (2012). www.fasebj.org