Increased Autophagy in Placentas of Intrauterine Growth-Restricted Pregnancies

Abstract

BackgroundUnexplained intrauterine growth restriction (IUGR) may be a consequence of placental insufficiency; however, its etiology is not fully understood. We surmised that defective placentation in IUGR dysregulates cellular bioenergic homeostasis, leading to increased autophagy in the villous trophoblast. The aims of this work were (1) to compare the differences in autophagy, p53 expression, and apoptosis between placentas of women with normal or IUGR pregnancies; (2) to study the effects of hypoxia and the role of p53 in regulating trophoblast autophagy; and (3) to investigate the relationship between autophagy and apoptosis in hypoxic trophoblasts.Methodology/Principal FindingsCompared with normal pregnant women, women with IUGR had higher placental levels of autophagy-related proteins LC3B-II, beclin-1, and damage-regulated autophagy modulator (DRAM), with increased p53 and caspase-cleaved cytokeratin 18 (M30). Furthermore, cytotrophoblasts cultured under hypoxia (2% oxygen) in the presence or absence of nutlin-3 (a p53 activity stimulator) had higher levels of LC3B-II, DRAM, and M30 proteins and increased Bax mRNA expression compared with controls cultured under standard conditions. In contrast, administration of pifithrin-α (a p53 activity inhibitor) during hypoxia resulted in protein levels that were similar to those of the control groups. Moreover, cytotrophoblasts transfected with LC3B, beclin-1, or DRAM siRNA had higher levels of M30 compared with the controls under hypoxia. However, transfection with Bcl-2 or Bax siRNA did not cause any significant change in the levels of LC3B-II in hypoxic cytotrophoblasts.Conclusions/SignificanceTogether, these results suggest that there is a crosstalk between autophagy and apoptosis in IUGR and that p53 plays a pivotal and complex role in regulating trophoblast cell turnover in response to hypoxic stress.

Autophagy in the placenta of women with hypertensive disorders in pregnancy

“…There were two previous reports regarding autophagy in the placenta of women complicated with hypertensive disorders in pregnancy [3,5]. The first report by Oh et al…”

“…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].…”

“…Two of these reports dealt with placentas of women with 65 preeclampsia (PE) [3,5]. However, the results were inconsistent: one suggested increased autophagy in PE [3], while the other did not [5].…”

“…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.…”

Selective intrauterine growth restriction in monochorionic-diamniotic twins: diagnosis and management

“…La actividad de autofagia es aumentada por el hambre, la privación del factor de crecimiento y la hipoxia 29 . Hung et al 30 demostraron una mayor actividad de autofagia en las placentas de embarazos únicos con RCIU mediante la cuantificación de la proteína placentaria LC3-II. En tanto Chang et al 31 de un total de 40 gestaciones MC, 21 de ellas afectadas de RCIUs y otras 19 aparentemente sanas, reportaronmayores niveles de LC3-II en el grupo con RCIUs (2,26 vs 1,04 p=0,02) y además, de acuerdo a los hallazgos del Doppler, cuando este se encontraba alterado al cotejarlo con aquellas gestaciones consideradas como sin RCIUs, también había un incremento de la misma (2,58 vs 1,04 p<0,05).…”