Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia

Abstract

The pregnancy complications of unexplained intrauterine growth restriction and early onset preeclampsia are thought to share a common aetiology in placental malperfusion secondary to deficient maternal spiral artery conversion. A key question is whether the contrasting clinical manifestations reflect different placental pathologies, or whether they are due to altered maternal responses to a common factor derived from the placenta. Recently, molecular evidence of protein synthesis inhibition secondary to endoplasmic reticulum stress has provided an explanation for the small placental phenotype in both conditions. However, other pathways activated by more severe endoplasmic reticulum stress are only observed in placentas from pregnancies associated with early onset preeclampsia. Here, we review the literature and conclude that there is evidence of greater maternal vascular compromise of the placenta in these cases. We speculate that in cases of normotensive intrauterine growth restriction the placental pathology is centred predominantly around endoplasmic reticulum stress, whereas in cases complicated by preeclampsia oxidative stress is further superimposed. This causes the release of a potent mix of pro-inflammatory cytokines, anti-angiogenic factors and trophoblastic aponecrotic debris into the maternal circulation that causes the peripheral syndrome. Maternal and fetal constitutional factors may modulate how the placenta responds to the maternal vascular insult, and how the mother is affected by the placental factors released. However, the principal conclusion is that the difference between these two conditions lies in the severity of the initiating deficit in spiral arterial conversion, and the relative degrees of endoplasmic reticulum stress and oxidative stress induced in the placenta as a result.

Fig. 1

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).

Fig. 2

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 24 h; B) exposure to a low dose (0.31 μg/ml) for 6–48 h. Adapted from Ref.  with permission of the American Society of Investigative Pathology.

Fig. 3

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.