Differences in Apoptotic Susceptibility of Cytotrophoblasts and Syncytiotrophoblasts in Normal Pregnancy to Those Complicated with Preeclampsia and Intrauterine Growth Restriction

Abstract

Placental apoptosis is increased in vivo in preeclampsia (PE) and intrauterine growth restriction (IUGR). The cause and pathological implications of this phenomenon are unknown. This study considers the apoptotic susceptibility of villous trophoblasts from normal, PE, and IUGR pregnancies. Cultured cytotrophoblasts (CTs) and an in vitro model of syncytialization were used. CTs were isolated from term placentas of 12 normal, 12 PE, and 12 IUGR pregnancies. Apoptosis was determined by terminal dUTP nick-end labeling (TUNEL), Annexin V binding, and ADP:ATP ratios. Cells were stimulated with tumor necrosis factor-alpha/interferon-gamma or reduced oxygen (<5 KPa). For CTs, ADP:ATP <1 correlates with Annexin V binding. For normal pregnancy, tumor necrosis factor-alpha and depleted oxygen significantly increased TUNEL, Annexin V binding and ADP:ATP in CTs and syncytiotrophoblasts (STs). Spontaneous apoptosis was similar between groups for both cell types. After stimulation, TUNEL and Annexin V binding of CTs were significantly raised in PE and IUGR as compared with normal pregnancy. After oxygen reduction, ADP:ATP in CTs and STs were significantly elevated in IUGR. TUNEL was also increased in STs in PE after oxygen depletion and was significantly raised in STs from IUGR pregnancies after stimulation with both agonists. This is the first description of enhanced apoptosis in isolated villous trophoblasts in PE and IUGR. These intrinsic differences may represent an important factor in the pathophysiology of these conditions.

A novel Mtd splice isoform is responsible for trophoblast cell death in pre-eclampsia

“…Increased Mtd-P expression in pre-eclampsia may be causative for increased trophoblast cell death and shedding observed in this disease. 7,9,[14][15][16]24,25 Our data are, to our knowledge, the first evidence of an expressional difference of a proapoptotic Bcl-2 family member in placentae of preeclamptic versus age-matched control subjects. Previous studies have demonstrated expressional differences of other apoptotic-related molecules in pre-eclamptic and control subjects including elevated expression of serum Fas and elevated placental expression of FasL and p53 in preeclamptic placentae.…”

“…Previous studies have demonstrated that under hypoxia, primary CT cells, particularly populations isolated from pre-eclamptic placentae, exhibit increased levels of apoptosis. 25,36 Importantly, reduced uter-oplacental oxygenation and hypoxia-reoxygenation, a direct cause of oxidative stress as it may be the case in early severe onset pre-eclampsia, are potent inducers of villous trophoblast cell death. 20 Our data herein corroborate these findings.…”

Sphingosine-1-phosphate inhibition of placental trophoblast differentiation through a Gi-coupled receptor response

“…Abnormal differentiation is one of the features of the villous trophoblast of placentas from pregnancies complicated by preeclampsia and the intrauterine growth restriction that accompanies it (12)(13)(14)(15)(16). Platelet activation is another characteristic of preeclampsia (17) and is a major source of intravascular S1P (18).…”

Chlamydia Heat Shock Protein 60 Induces Trophoblast Apoptosis through TLR4

“…Our data suggest that cHSP60-induced trophoblast apoptosis at this early stage may have a significant impact on placental and fetal development, and consequently pregnancy outcome. Indeed, trophoblast apoptosis is increased in pregnancies complicated by preeclampsia and intrauterine growth restriction and are often associated with insufficient trophoblast invasion (57)(58)(59).…”