Preeclampsia is a dangerous cardiovascular disorder affecting 5-8% of pregnancies and a leading cause of maternal and neonatal death globally. The only cure currently available is delivery of the baby, often pre-term. Although the pathogenesis of preeclampsia is poorly understood, angiogenic imbalance is a hallmark feature. In this project, we aimed to evaluate potential preeclampsia therapeutics, including exercise, metformin and a novel FKBPL-based therapeutic peptide, AD-01, in an in vivo model of angiogenic imbalance.
A non-viral gene delivery system, RALA, was used to overexpress sFlt-1. Wild-type (WT) and fkbpl+/- C57BL/6N mice were administered RALA-sFlt-1 nanoparticle on embryo day (E)8 and 12 and randomly allocated to groups received the following interventions: i) control, ii) exercise, iii) metformin (200 mg/kg/day via drinking water) or iv) AD-01 (0.003mg/kg/day). Blood pressure and heart rate were measured using the tail-cuff method every two days from E8. Echocardiography and placenta/embryo weight were determined on E18.
Nanoparticles (sFlt1-RALA) showed a satisfactory profile with particle size <100 nm, charge between 40-60 mV, and good uniformity of nanoparticle size distribution. Low background fkbpl appears to negatively impact pup weight in the AD-01 but not in the metformin and exercise treatment group, which is more pronounced in male pups (p<0.05). However, placental weight was not affected by FKBPL genotype or AD-01, metformin or exercise treatment. Blood pressure was not affected by any treatments compared to physiological pregnancy control. Cardiac output was reduced in fkbpl+/- control (P<0.05) and WT exercise groups (p<0.01), whereas stroke volume was only reduced in the latter group, compared to their relative control.
In conclusion, in our preeclampsia model of angiogenic imbalance, differences were observed between experimental groups, which were also dependent on FKBPL genotype, depicting an important role of FKBPL as a therapeutic target in preeclampsia.