Kong Hongfang, Ma Xuyuan, Wang Fang, Su Yuan, Chang Yaqing, Xin Hong
Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, No. 215 Heping Xi Road, Shijiazhuang, 050000, Hebei, China.
Sci Rep. 2025 Apr 6;15(1):11752. doi: 10.1038/s41598-025-96819-5.
Preeclampsia (PE) is a pregnancy-specific disorder characterized by multi-system involvement, leading to increased perinatal morbidity and mortality as well as long-term cardiovascular damage in both mother and fetus. This study aimed to investigate the alterations and potential role of high temperature requirement factor A4 (Htra4) in early-onset PE. We conducted a comparative analysis of the baseline data between patients with early-onset PE and normal controls, as well as analyzed the correlation of Htra4 levels in the peripheral blood with pregnancy outcomes. Additionally, we investigated the impact of recombinant protein Htra4 on human umbilical vein endothelial cells (HUVECs). Patients with early-onset PE patients exhibited cardiac, hepatic, and renal impairment, as well as elevated levels of Htra4 in peripheral blood but not in umbilical cord blood. Further correlation analysis reveals a significant association between peripheral blood Htra4 levels and adverse pregnancy outcomes in patients with early-onset PE, particularly a strong correlation between maternal blood Htra4 levels and systolic and diastolic blood pressure, suggesting that Htra4 may be associated with impaired vascular function. Histopathological examination revealed inadequate trophoblast cell invasion in the decidua of early-onset PE patients, along with unsuccessful uterine artery remodeling. Additionally, the spiral arterial lumen in the decidua exhibited narrower and irregularly shaped remodeling. Immunofluorescence localization demonstrated the expression of Htra4 in trophoblasts of villous as well as extra-villous lineages. We observed intensified Htra4 staining in the placenta and decidua tissues of patients with early-onset PE. In combination with the pathological alterations of decidual vessels, it is hypothesized that Htra4 might be related to the dysfunction of endothelial cells. Subsequent research indicated that Htra4 induce the onset of oxidative stress, and inflammatory response in HUVECs, suggesting a potential association between the elevated Htra4 levels and vascular endothelial injury in patients with early-onset PE. This study identified a correlation between Htra4 and adverse pregnancy outcomes in patients with early-onset PE, potentially leading to vascular endothelial injury through elevated levels of Htra4.
子痫前期（PE）是一种妊娠特有的疾病，其特征为多系统受累，导致围产期发病率和死亡率增加，以及母亲和胎儿的长期心血管损害。本研究旨在探讨高温需求因子A4（Htra4）在早发型PE中的变化及潜在作用。我们对早发型PE患者和正常对照者的基线数据进行了比较分析，并分析了外周血中Htra4水平与妊娠结局的相关性。此外，我们研究了重组蛋白Htra4对人脐静脉内皮细胞（HUVECs）的影响。早发型PE患者表现出心脏、肝脏和肾脏损害，外周血中Htra4水平升高，但脐带血中未升高。进一步的相关性分析显示，早发型PE患者外周血Htra4水平与不良妊娠结局之间存在显著关联，尤其是母体血液Htra4水平与收缩压和舒张压之间存在强烈相关性，提示Htra4可能与血管功能受损有关。组织病理学检查显示，早发型PE患者蜕膜中滋养层细胞浸润不足，子宫动脉重塑未成功。此外，蜕膜中的螺旋动脉腔呈现出更窄且形状不规则的重塑。免疫荧光定位显示Htra4在绒毛和绒毛外谱系的滋养层细胞中表达。我们观察到早发型PE患者的胎盘和蜕膜组织中Htra4染色增强。结合蜕膜血管的病理改变，推测Htra4可能与内皮细胞功能障碍有关。随后的研究表明，Htra4诱导HUVECs发生氧化应激和炎症反应，提示早发型PE患者中Htra4水平升高与血管内皮损伤之间可能存在关联。本研究确定了早发型PE患者中Htra4与不良妊娠结局之间的相关性，Htra4水平升高可能导致血管内皮损伤。
