SIRT1 regulates trophoblast senescence in premature placental aging in preeclampsia

Introduction: Premature placental aging is implicated in a number of complications of pregnancy including preeclampsia. A placenta knockout mouse model has shown a relationship between SIRT1, aging and placental dysfunction. The role of SIRT1 in cellular senescence has been extensively studied in various cell types, but its role in trophoblast senescence is almost unknown. Methods: Human placental samples were obtained from preeclampsia-affected women and healthy controls. The placental aging profiles were assessed by Doppler ultrasound, placental histopathology, and evaluation of senescence- and ECM-related markers. The SIRT1 expression pattern relevant to placental aging profiles was studied in premature aging placenta with preeclampsia (32-37 weeks gestation, n = 10) and healthy controls (37-40 weeks gestation, n = 10). Using cell culture, the effects of activation and knockdown of SIRT1 or its downstream target molecules in syncytialized BeWo cells were evaluated. Results: SIRT1 was expressed by syncytiotrophoblast across normal gestation. In preeclamptic premature aging placentas, SIRT1 was significantly downregulated, while senescence- and extracellular matrix (ECM)-related protein levels were upregulated compared to controls. Immunohistochemistry showed these changes to be confined to syncytiotrophoblast. In vitro, SIRT1 activation in response to resveratrol (RSV) abrogated senescence in forskolin-induced syncytialization of BeWo cells via regulation of senescence- and ECM-related proteins, and filamentous actin (F-actin). These effects were restored by SIRT1 siRNA. Discussion: The downregulation of SIRT1 may accelerate senescence of syncytiotrophoblast via targets contributing to regulation of the cell cycle, ECM production and cytoskeleton reorganization leading to premature placental aging observed in preeclampsia.