Identification of autophagic vacuoles and regulators of autophagy in villous trophoblast from normal term pregnancies and in fetal growth restriction

Abstract

Fetal growth restriction (FGR) is a serious pregnancy complication associated with increased perinatal mortality and morbidity. Although the majority of cases with FGR result from placental dysfunction, the pathophysiology is incompletely understood. Autophagy is a physiological form of cell degradation exacerbated by nutrient and oxygen restriction, which are both thought to play a role in the aetiology of FGR. We hypothesized that autophagy is present in the normal human placenta and is exaggerated in FGR. Autophagy was assessed in electron micrographs from normal and FGR placentas and by Western blotting for LC3B and LAMP-2. The localization of regulators of autophagy was examined by immunohistochemistry. Culture of BeWo cells was used to investigate whether nutrient and/or oxygen deprivation can induce autophagy in trophoblast. Autophagy predominantly localized to the syncytiotrophoblast layer and autophagosomes were more frequent in FGR. The regulators LAMP-2, LC3B, Beclin-1, ATG 5, ATG9 and ATG16L1 were all present in villous trophoblast. LAMP-2 immunostaining was more punctate in FGR. In BeWo cells, culture in reduced oxygen tension and/or serum depleted conditions led to the appearance of autophagosomes which was associated with changes in LAMP-2 configuration. We conclude that autophagy in human term placenta may be involved in the placental dysfunction present in FGR.

Ultrastructure of the placenta in gestational diabetes mellitus

“…So, in the context of disease, vacuolation is observed as a response to stress and oxygen restriction. [2,21,22] Regarding the villous core, the present study showed that edematous spaces were obviously seen in women with GDM. Gauster et al [23] and Slukvin et al [13] mentioned that the placental villi showed spaces consistent with villous edema in GDM women.…”

“…It was hypothesized that a slight vacuolation may be present in the normal human placenta as a natural and physiological form of cell degradation which promotes survival. [20,21] Meng et al [2] found much more trophoblastic vacuoles in placentas of GDM compared to controls. [2] Hyperglycemia and hypoxia which have a role in the etiology of GDM may enhance the lysosome/vacuole functions of the trophoblasts, which result in widespread cytoplasmic vacuolation and altered transplacental metabolic exchange that may lead to cell death.…”

Autophagy regulation of physiological and pathological processes in the female reproductive tract

“…Higher number of autophagosomes were found in IUGR placentas in the villi. 44 Chang et al 45 studied IUGR in monochorionic twins and found that LC3-II expression was much higher in a twin with IUGR.…”

Autophagy in the placenta of women with hypertensive disorders in pregnancy

“…However, the results were inconsistent: one suggested increased autophagy in PE [3], while the other did not [5]. Three reports dealt with placentas in cases of fetal growth restriction (FGR) [5,7,8], and all three suggested increased autophagy in placentas with FGR.…”

“…As autophagy has only recently been identified in the human placenta [3], to our knowledge, there have been only eight reports dealing with autophagy in the human placenta [3, 4,5,6,7,8,9,10]. Two of these reports dealt with placentas of women with 65 preeclampsia (PE) [3,5].…”