From the International Peace Maternity and Child Health Hospital (B.H., X.Y., Y.L., D.H., W.Y., H.Z., W.C.), Institute of Embryo-Fetal Original Adult Disease (X.Y.), and Department of Obstetrics and Gynecology, Xinhua Hospital (X.X.), School of Medicine, Shanghai Jiao Tong University, China; State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science (Y.D., Z.C.); and School of Life Science and Technology, Shanghai Tech University, China (Z.C.).
Hypertension. 2018 Apr;71(4):671-680. doi: 10.1161/HYPERTENSIONAHA.117.10510. Epub 2018 Feb 5.
Preeclampsia is a common pregnancy-specific disorder characterized by elevated blood pressure and proteinuria. Activation of the maternal immune system and impaired placental angiogenesis are thought to contribute to the pathogenesis of preeclampsia. TLR9 (Toll-like receptor 9) plays a role in innate immunity, defending the organism against infection. The purpose of this study was to determine whether TLR9 inhibits angiogenesis at the fetomaternal interface under conditions of preeclampsia. We confirmed the downregulation of VEGFA (vascular endothelial growth factor A) and upregulation of TLR9 and sFLT1 (soluble vascular endothelial growth factor receptor 1) in placentas from preeclamptic women. Then, we established a mouse model with preeclampsia-like symptoms using the synthetic TLR9 agonist CpG (cytidine-phosphate-guanosine)-ODN (oligodeoxynucleotide; ODN1826). We observed the downregulation of VEGFA and the upregulation of sFLT1 in placentas from the preeclampsia-like animal model and in trophoblasts treated with CpG-ODN (ODN2006). In addition, silencing TLR9 promoted the migration and invasion of HTR8/SVneo cells. In conclusion, TLR9 is capable of robustly suppressing angiogenesis by differentially regulating the expression of VEGFA and sFLT1 at the fetomaternal interface, potentially contributing to the development of preeclampsia.
子痫前期是一种常见的妊娠特有疾病，其特征为血压升高和蛋白尿。母体免疫系统的激活和胎盘血管生成受损被认为是子痫前期发病机制的一部分。TLR9（Toll 样受体 9）在先天免疫中发挥作用，保护机体免受感染。本研究旨在确定 TLR9 在子痫前期时是否会抑制胎儿-母体界面的血管生成。我们证实了子痫前期妇女胎盘 VEGFA（血管内皮生长因子 A）下调和 TLR9、sFLT1（可溶性血管内皮生长因子受体 1）上调。然后，我们使用合成 TLR9 激动剂 CpG（胞嘧啶磷酸鸟嘌呤）-ODN（寡脱氧核苷酸；ODN1826）建立了具有子痫前期样症状的小鼠模型。我们观察到子痫前期样动物模型和 CpG-ODN（ODN2006）处理的滋养层中 VEGFA 下调和 sFLT1 上调。此外，沉默 TLR9 促进了 HTR8/SVneo 细胞的迁移和侵袭。总之，TLR9 通过差异调节胎儿-母体界面 VEGFA 和 sFLT1 的表达，能够强有力地抑制血管生成，可能导致子痫前期的发生。
