Lightning Talk + Poster ESA-SRB-ANZOS 2025 in conjunction with ENSA

Evaluating Therapeutic Strategies for Maternal Cardiovascular Dysfunction in a Nanoparticle-Induced Mouse Model of Preeclampsia (128576)

Fatemeh FH Heidari 1 2 , Iman Akbarzadeh 1 2 , Tracy Robson 3 , Helen McGrathy 4 , Elaine Gilmore 4 , Kristine McGrath 1 , Lana McClements 1 2
  1. School of Life science, University of Technology Sydney, Sydney, NSW, Australia
  2. Institute for Biomedical Materials and Devices, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
  3. School of Pharmacy and Biomolecular Sciences, University of Medicine and Health Sciences, Dublin, Ireland, UK
  4. School of Pharmacy, Queen's University Belfast, Belfast , Northern Ireland, UK

Introduction
Preeclampsia is a dangerous cardiovascular disorder of pregnancy and a leading cause of maternal and neonatal death globally. Although the pathogenesis is poorly understood, angiogenic imbalance is a hallmark feature. We aimed to elucidate the impact of angiogenic imbalance (high sFlt-1/low FKBPL) on the maternal cardiovascular system during pregnancy and to evaluate potential treatments in an established in vivo model1.

Methods
Wild-type (WT) and fkbpl+/- C57BL/6N mice were administered RALA-sFlt-1 (5μg) nanoparticles intravenously on embryo day (E)8 and 12 and randomly allocated to i) control (100μl, n=10), ii) exercise (n=5), iii) metformin (200 mg/kg/day via drinking water, n=7) or iv) AD-01 (0.003mg/kg/day, n=8). Blood pressure and heart rate were measured using the tail-cuff method every two days from E8. Echocardiography and placenta/embryo weight were determined, and tissues were harvested on E18 for analysis.

Results
Nanoparticles (sFlt1-RALA) showed satisfactory size (<100 nm), charge (40–60 mV), and excellent uniformity. In WT mice, pregnancy increased cardiac output vs. non-pregnant controls (p<0.0081). sFlt-1 overexpression reduced cardiac output vs. vehicle controls (p<0.044), while exercise restored it (p<0.0015) and metformin showed a trend toward improvement (p<0.054). In fkbpl+/- mice, exercise showed a trend toward rescuing sFlt-1-induced cardiac output reduction (p<0.065). At GD12, fkbpl+/- mice with sFlt-1 overexpression in the exercise group showed significant improvements in systolic (p<0.027), diastolic (p<0.031), and mean (p<0.028) arterial pressure, compared to sFlt-1 fkbpl+/- controls. ELISA showed a significant reduction in cardiac sFlt-1 protein in metformin-treated sFlt-1 fkbpl+/- mice (p<0.035). Uterine artery resistance and pulsatility indices were not significantly altered across treatment groups.

Conclusion
Our nanoparticle-induced preeclampsia model of angiogenic imbalance, driven by high sFlt-1 and/or low fkbpl expression, adversely impacts the maternal cardiovascular system. Exercise and metformin show therapeutic potential in reversing dysfunction, which is clearly fkbpl genotype dependent.

  1. McNally, R., Alqudah, A., McErlean, E. M., Rennie, C., Morshed, N., Short, A., … McClements, L. (2021). Non-Viral Gene Delivery Utilizing RALA Modulates sFlt-1 Secretion, Important for Preeclampsia. Nanomedicine, 16(22), 1999–2012. https://doi.org/10.2217/nnm-2021-0180