Abstract Body: Background: Preeclampsia (PE) significantly impacts maternal and perinatal health worldwide. Despite limited treatment options, predictive tests could help in early diagnosis and personalized treatment/prevention strategies. Current biomarker, such as soluble fms-like tyrosine kinase-1 (sFlt-1) and placenta growth factor (PIGF) offer reasonable negative predictive values, but their use as positive predictive markers is limited. Using unbiased discovery proteomics on urine extracellular vesicles (EV), followed by verification by ELISA and western blotting we identified a novel biomarker candidate for PE, vasorin (VASN), which is significantly decreased in PE, along with a known mediator of PE, angiotensinogen (AGT), that was significantly increased in PE as biomarker candidates.
Hypothesis: Levels of AGT, VASN and their ratios in peripheral blood can be utilized as biomarkers for PE.
Goals/Aims: 1) To determine gestational age (GA)-dependence of AGT, VASN and AGT/VASN plasma levels in human and murine pregnancy. 2) To assess disease association of AGT, VASN and AGT/VASN in a cohort of pregnant women with PE with severe features (sPE) and gestational age-matched normotensive pregnant women (NTP) and in a murine model of PE.
Methods: Plasma was collected from GA-matched NTP and sPE. Timed pregnant mice were injected with adenoviral vector (AD) encoding sFLT-1 on embryonic day 10.5 (mouse PE), or with AD encoding enhanced green fluorescent protein injection (mouse control). AGT and VASN were measured by ELISA in human samples and were quantified by western blotting in murine samples.
Results: AGT and AGT/VASN showed negative correlations with GA, while VASN levels showed positive correlation with GA in NTP and in mouse controls. PlGF and sFLT-1 levels had weak/no correlations with GA. AGT and AGT/VASN were significantly higher in sPE and mouse PE, while VASN was significantly decreased in sPE and mouse PE as compared to NTP and mouse controls, respectively. To differentiate between sPE vs NTP with receiver operating characteristic curve (ROC) for AGT/VASN: AUC (0.90), Sensitivity =92%, Specificity = 85% at AGT/VASN>81.6.
Conclusion: AGT and AGT/VASN ratio increase, and VASN decrease can serve as biomarkers for PE.