Overexpressed Trophoblast Glycoprotein Contributes to Preeclampsia Development by Inducing Abnormal Trophoblast Migration and Invasion Toward the Uterine Spiral Artery

子痫前期 螺旋动脉 滋养层 胎盘 生物 男科 基因敲除 胎盘形成 细胞生物学 医学 怀孕 基因 胎儿 遗传学
作者
Lu Sun,Meiting Shi,Jian Wang,Xiaoxue Han,Jiachun Wei,Zhengrui Huang,Xiaofeng Yang,Yuzhen Ding,Ping Zhang,Andong He,Mengyuan Liu,Ruiling Yan,Xuesong Yang,Ruiman Li,Guang Wang
出处
期刊:Hypertension [Ovid Technologies (Wolters Kluwer)]
卷期号:81 (7): 1524-1536
标识
DOI:10.1161/hypertensionaha.124.22923
摘要

BACKGROUND: Preeclampsia is a significant pregnancy disorder with an unknown cause, mainly attributed to impaired spiral arterial remodeling. METHODS: Using RNA sequencing, we identified key genes in placental tissues from healthy individuals and preeclampsia patients. Placenta and plasma samples from pregnant women were collected to detect the expression of TPBG (trophoblast glycoprotein). Pregnant rats were injected with TPBG-carrying adenovirus to detect preeclamptic features. HTR-8/SVneo cells transfected with a TPBG overexpression lentiviral vector were used in cell function experiments. The downstream molecular mechanisms of TPBG were explored using RNA sequencing and single-cell RNA sequencing data. TPBG expression was knocked down in the lipopolysaccharide-induced preeclampsia-like rat model to rescue the preeclampsia features. We also assessed TPBG’s potential as an early preeclampsia predictor using clinical plasma samples. RESULTS: TPBG emerged as a crucial differentially expressed gene, expressed specifically in syncytiotrophoblasts and extravillous trophoblasts. Subsequently, we established a rat model with preeclampsia-like phenotypes by intravenously injecting TPBG-expressing adenoviruses, observing impaired spiral arterial remodeling, thus indicating a causal correlation between TPBG overexpression and preeclampsia. Studies with HTR-8/SVneo cells, chorionic villous explants, and transwell assays showed TPBG overexpression disrupts trophoblast/extravillous trophoblast migration/invasion and chemotaxis. Notably, TPBG knockdown alleviated the lipopolysaccharide-induced preeclampsia-like rat model. We enhanced preeclampsia risk prediction in early gestation by combining TPBG expression with established clinical predictors. CONCLUSIONS: These findings are the first to show that TPBG overexpression contributes to preeclampsia development by affecting uterine spiral artery remodeling. We propose TPBG levels in maternal blood as a predictor of preeclampsia risk. The proposed mechanism by which TPBG overexpression contributes to the occurrence of preeclampsia via its disruptive effect on trophoblast and extravillous trophoblast migration/invasion on uterine spiral artery remodeling, thereby increasing the risk of preeclampsia.
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