Integrated molecular and histological profiling of preeclampsia suggests angiogenic dysregulation associated with maternal and fetal outcomes.

Preeclampsia (PE) is a potentially life-threatening multisystem disorder affecting maternal and fetal health and is associated with impaired angiogenesis, endothelial dysfunction, inflammation, and apoptosis. In this study, we characterized molecular, histopathological, and clinical alterations in placentas from 30 women with PE compared with 30 normotensive controls. Placental tissues underwent macroscopic evaluation, histopathology, immunohistochemistry for α-Klotho, endothelial nitric oxide synthase (eNOS), vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and tumor necrosis factor-α (TNF-α), alongside TUNEL assay for apoptosis. PE pregnancies were associated with earlier delivery, lower neonatal birth weight, reduced placental weight and volume, and decreased maternal total protein and albumin levels. Histologically, PE placentas exhibited increased syncytial knots, intervillous fibrin deposition, distal villous hypoplasia, chorangiosis, avascular villi, and calcifications. Immunohistochemical analyses indicated reduced expression of α-Klotho, eNOS, VEGF, and PlGF, with increased TNF-α expression and higher apoptotic index. α-Klotho expression correlated positively with angiogenic markers, placental weight, and birth weight, and negatively with TNF-α and apoptosis. Multivariate regression analyses suggested that PE is associated with increased placental apoptosis and TNF-α expression, as well as reduced α-Klotho, eNOS, VEGF, and PlGF expression, and with lower birth weight, primarily mediated by prematurity. Early-onset PE exhibited more pronounced α-Klotho reduction with relatively preserved eNOS expression, suggesting potential compensatory endothelial responses, while magnesium sulfate or antihypertensive therapy did not significantly influence molecular profiles. These findings suggest that PE is linked to coordinated alterations in angiogenic, endothelial, and inflammatory pathways associated with placental structural changes and adverse perinatal outcomes. Observed alterations in α-Klotho and angiogenic markers highlight potential pathways for further investigation into targeted molecular interventions. This study is limited by its single-center, and relatively small sample size, which may limit generalizability, and causal relationships cannot be established; further multi-center prospective studies are warranted.