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The Role of Apoptosis in the Regulation of Trophoblast Survival and Differentiation during Pregnancy

Department of Molecular, Cellular and Developmental Biology (S.L.S.-C.), Yale University, New Haven, Connecticut 06520; and Department of Obstetrics, Gynecology and Reproductive Sciences (V.M.A., G.M.), Yale University School of Medicine, New Haven, Connecticut 06520

Correspondence: Address all correspondence and requests for reprints to: Gil Mor, M.D., Ph.D., Department of Obstetrics, Gynecology and Reproductive Sciences, Reproductive Immunology Unit, Yale University School of Medicine, 333 Cedar Street FMB 301, New Haven, Connecticut 06520. E-mail: Gil.Mor{at}yale.edu

Apoptosis is important for normal placental development, but it may also be involved in the pathophysiology of pregnancy-related diseases. Normal placental development is dependent upon the differentiation and invasion of the trophoblast, the main cellular component of the placenta. Trophoblast apoptosis increases in normal placentas as gestation proceeds, and a greater incidence of trophoblast apoptosis has been observed in pregnancies complicated by preeclampsia or intrauterine growth retardation (IUGR). In response to different stimuli, apoptosis may be initiated extrinsically by the death receptor pathway or intrinsically by the mitochondrial pathway. The central executioners of apoptosis are the caspases, which cleave numerous vital cellular proteins to affect the apoptotic cascade. By inhibiting caspase activation, several endogenous inhibitors, including flice-like inhibitory proteins (FLIPs), inhibitors of apoptosis (IAPs), and antiapoptotic Bcl-2 family members, can prevent further propagation of the death signal. Macrophages present at the maternal-fetal interface may also contribute to trophoblast survival by removing apoptotic cells and producing cytokines and growth factors, which influence the progression of the apoptotic cascade. This review focuses on the role of apoptosis in trophoblast development and differentiation, the molecular mechanisms by which normal trophoblast apoptosis can occur, and how it is regulated to prevent excessive trophoblast apoptosis and possible pregnancy complications.

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