Trophoblast Apoptosis and Complicated Pregnancies

A greater incidence of villous9"12 as well as extravillous13, 4 trophoblast apoptosis has been detected in placentas from pregnancies complicated by preeclampsia or IUGR. This increase in trophoblast cell death might explain the insufficient trophoblast invasion often found in abnormal pregnancies. If increased trophoblast apoptosis occurs early in pregnancy, it may limit interstitial and endovascular invasion by extravillous trophoblasts.1 14,11 However, a recent study by Kadyrov et al, suggests that the reduced trophoblast invasion observed in preeclampsia is not associated with higher rates of apoptosis since a decrease in interstitial trophoblast apoptosis was observed in preeclamptic placentas compared to the normal controls.111 This could be the result of when the samples were analyzed. The samples evaluated in this study were obtained from patients with active disease and, therefore, the presence of apoptotic cells may have preceded the time of analysis. Nevertheless, the original studies also demonstrated that the apoptotic extravillous cytotrophoblast cells in preeclamptic samples were negative for Bcl-2 expression.13,14 Similarly, the expression of Bcl-2 was also shown to be less abundant in syncytiotrophoblasts from severe preeclamptic and IUGR placentas,12 whereas earlier studies found no difference in Bcl-2 expression, as well as in the expression of Bc1-xl, Bax and Bak in placental villi from complicated and normal pregnancies,9, Levy et al, however, did find that the expression of p53, a tumor suppressor that activates pro-apoptotic Bcl-2 family members such as Bax in response to DNA damage,113 was upregulated in villous tissue from IUGR placentas.112

The elevated trophoblast apoptosis observed in pregnancies complicated by preeclampsia and IUGR is thought to be the result of placental oxidative stress, which may, in part, be triggered by hypoxia.114,115 Although there is some discrepancy as to whether trophoblast cells are sensitive to hypoxia-induced apoptosis,59,116,117 hypoxia induces apoptosis in other cell types118,119 and the mechanism by which hypoxia mediates its effects has been shown to involve the mitochondrial pathway.120 Indeed, it was previously shown that hypoxia enhances apoptosis in term trophoblasts by decreasing the expression of Bcl-2 while increasing the expression of p53 and Bax and that EGF significantly lowered the level of hypoxia-induced apoptosis.11 Moreover, a subsequent study with a first trimester extravillous trophoblast cell line demonstrated that caspase-3 and caspase-9 activation increases over time under hypoxic conditions and that EGF protects trophoblast cells from hypoxia by preventing the cleavage of caspase-3 even in the presence of a phosphatidyl-inositol-3-kinase (PI3K) inhibitor, suggesting that EGF exerts its anti-apoptotic effect independently of the PI3K/protein kinase B (Akt) survival pathway.121

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