Htra4 promotes vascular endothelial cell injury and is associated with the early-onset of preeclampsia

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.