Preeclampsia is a major cause of maternal and perinatal morbidity and mortality, with late-onset disease (LOPE) accounting for 80% of cases. Reliable early prediction and prevention of LOPE remains unavailable due to our limited understanding of its pathogenesis. The placenta plays a central role in preeclampsia.
Our proteomic analysis of early placental biopsies identified that low-density lipoprotein receptor-related protein-associated protein (LRPAP) 1 expression was reduced in pregnancies that developed LOPE. However, the role of LRPAP1 in placentation remains unknown. Here, we investigated its function using human and mouse models.
In humans, LRPAP1 was silenced (siRNA) in trophoblast progenitor cells prior to syncytialization, and gene expression assessed by RT-qPCR (N=5/group). LRPAP1 knockdown reduced the expression of syncytialization markers (βHCG, 0.6-fold; SDC1, 0.5-fold and syncytin1, 0.5-fold) and the angiogenic factor VEGF (0.7-fold), while increasing the expression of preeclampsia-associated markers (sFlt-1, 2.4-fold; ICAM1, 1.8-fold; IL6, 8.1-fold and IL18, 1.9-fold)(all p< 0.05).
In mice, placental LRPAP1 expression and localization were characterized throughout gestation by RT-qCPR and immunohistochemistry. LRPAP1 mRNA expression peaked at embryonic day(E) 15 and localized to multiple placental cell types. LRPAP1-null mice were born at 37% below the expected Mendelian ratio following heterozygous matings (p<0.05), suggesting prenatal lethality. Wild-type and LRPAP1-null matings (N=4/group) were assessed at E17 or allowed to deliver naturally with offspring monitored weekly until 10 weeks of age. At E17, LRPAP1-null placentas exhibited decreased vascular density (19 vs 15 vessels/սm2) and decreased placental and fetal weight (both 0.9-fold), together with upregulation of the oxidative stress-associated gene CYBA (1.8-fold) and the endothelial dysfunction marker VCAM1 (1.9-fold)(all p< 0.05). Male offspring from LRPAP1-null pregnancies exhibited reduced postnatal growth from postnatal day 21 onwards (p<0.05), whereas female offspring were unaffected.
Our findings identify LRPAP1 as an important regulator of normal placental function, providing insight into the pathophysiology of LOPE.