Placental Endoplasmic Reticulum Stress and Oxidative Stress in the Pathophysiology of Unexplained Intrauterine Growth Restriction and Early Onset Preeclampsia

Diagrammatic representation of the signalling pathways activated in the unfolded protein response following ER stress. The sensor molecules, PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring 1 (Ire1) and activating transcription factor 6 (ATF6), are transmembrane proteins normally held inactive by the binding of GRP78/BiP, but are released when the GRP78 preferentially binds to misfolded proteins accumulating in the ER lumen. The UPR aims to restore homeostasis within the ER, but there are also links to the inflammatory response through the Ire1 pathway and TNF receptor-associated factor 2 (TRAF2).

An illustration of the fact that the different signalling pathways comprising the UPR can be activated separately, and at different levels of ER stress, following treatment of JEG-3 cells with tunicamycin. A) Exposure to increasing doses of tunicamycin for 24h; B) exposure to a low dose (0.31μg/ml) for 6–48h. Adapted from Ref. [24] with permission of the American Society of Investigative Pathology.

Diagrammatic representation of how placental ER stress and oxidative stress may contribute to the pathophysiologies of IUGR and IUGR+PE. We speculate that in IUGR alone the pathology is predominantly based around ER stress, with homeostatic responses, in particular protein synthesis inhibition, being responsible for the small placental phenotype. When maternal vascular compromise is more severe placental oxidative stress may be superimposed, causing the additional release of a cocktail of pro-inflammatory factors that result in the peripheral syndrome of preeclampsia.