SIRT1 negatively regulates invasive and angiogenic activities of the extravillous trophoblast

Problem Dysregulation of extravillous trophoblast (EVT) invasion leads to pregnancy complications, such as pre‐eclampsia, fetal growth restriction, and placenta accreta. The aim of this study was to explore the role of SIRT1 in EVT invasion and its underlying mechanism. Method of study SIRT1‐specific siRNA was transfected into Swan 71 cells, an immortalized first trimester trophoblast cell line. The Boyden chamber invasion assay, the scratch wound healing assay, and cell proliferation assay were performed. The expression levels of epithelial‐to‐mesenchymal transition (EMT) markers, matrix metalloproteinase‐2 (MMP‐2), MMP‐9, p‐Akt, Akt, p‐p38MAPK, p38MAPK, p‐ERK, ERK, p‐JNK, JNK, Fas, and Fas ligand (FasL) were examined by western blot. Tube formation assay was conducted by using Matrigel. Results SIRT1 knockdown by siRNA significantly enhanced invasion and migration as well as the expression of MMP‐2, MMP‐9, and EMT markers in Swan 71 cells, but reduced proliferation. The effects of SIRT1 knockdown on invasion, migration, proliferation, and endothelial‐like tube formation in Swan 71 cells were reversely regulated by blockade of Akt and p38MAPK signaling. In addition, SIRT1 knockdown markedly promoted colocalization of Swan 71 cells to human umbilical vein endothelial cell (HUVEC) networks and induced reduction in Fas and enhancement of FasL. Conditioned media of SIRT1 knockdown‐Swan 71 cells caused reduction in cell proliferation and augmentation of cytotoxicity along with increased Fas expression in HUVECs. Conclusion Our results suggest that SIRT1 may be associated with placental development by controlling EVT invasion and spiral artery remodeling via modulation of EMT, MMP‐2, MMP‐9, Akt/p38MAPK signaling, and Fas/FasL.