The integrity of the feto-maternal interface is critical for survival of the 
conceptus. This interface, consisting of the maternal decidua and the invading 
placental trophoblast, is exposed to profound changes in oxygen tension during 
pregnancy. We demonstrate that human endometrial stromal cells become 
extraordinarily resistant to oxidative stress-induced apoptosis upon 
decidualization in response to cAMP and progesterone signaling. This 
differentiation process is associated with the induction of the forkhead 
transcription factor FOXO1, which in turn increases the expression of the 
mitochondrial antioxidant manganese superoxide dismutase. However, silencing of 
FOXO1 did not increase the susceptibility of decidualized cells to oxidative 
cell death. Comparative analysis demonstrated that hydrogen peroxide, a source 
of free radicals, strongly induces FOXO3a mRNA and protein expression in 
undifferentiated human endometrial stromal cells but not in decidualized cells. 
Expression of a constitutively active FOXO3a mutant elicited apoptosis in 
decidualized cells. Furthermore, silencing of endogenous FOXO3a in 
undifferentiated cells abrogated apoptosis induced by hydrogen peroxide. These 
results suggest that the induction of FOXO1 may enhance the ability of 
decidualized cells to prevent oxidative damage while the simultaneous repression 
of FOXO3a expression disables the signaling pathway responsible for oxidative 
cell death. The differential regulation of FOXO expression provides the decidua 
with a robust system capable of coping with prolonged episodes of oxidative 
stress during pregnancy.