Oral Presentation ESA-SRB 2023 in conjunction with ENSA

New FKBPL-targeting treatment for preeclampsia rescues first trimester trophoblast cell proliferation and endothelial cell dysfunction (#33)

Sahar Ghorbanpour 1 , Dinara Afrose 1 , Philip Hansbro 1 , Qian Peter Su 1 , Mary Meltem Kavurma 2 , Lana McClements 1
  1. University of Technology Sydney, Sydney, NSW, Australia
  2. Heart Research Institute, University of Sydney, Sydney, NSW, Australia

Preeclampsia is the leading cause of mortality and morbidity in pregnancy, and, still, it is a condition without a cure. Aberrant placental development and growth due to inappropriate trophoblast and/or endothelial cell (EC) function, are the underlying causes. FK506-binding protein like (FKBPL) is emerging as an important mechanism in the pathogenesis of preeclampsia1 and a predictive and diagnostic biomarker2. In this study, we aimed to determine whether the FKBPL-based therapeutic mimetic peptide, AD-01, can abrogate impairment in trophoblast proliferation, oxidative stress and EC migration in vitro, in 2D and 3D microfluidic models of preeclampsia.

First trimester trophoblast cells, ACH-3Ps, were exposed to various preeclamptic stimuli in 2D, including hypoxia (dimethyloxalylglycine, DMOG, 1 mM), inflammation (tumour necrosis factor, TNF-α, 10 ng/ml) or mitochondrial dysfunction (Rho-6G, 1 μg/ml). AD-01 (100 mM), was added as a treatment at the same time, for 48 h. Trophoblast proliferation and uric acid concentrations were measured using MTT and Uric Acid Assay Kit, respectively. Human microvascular endothelial cells (HMEC-1) were treated ± FKBPL siRNA or exposed to inflammatory or hypoxic conditions using macrophage-condition medium (MCM) or DMOG (1mM), respectively, ± AD-01 (100mM). A 3D microfluidics chip was developed. EC migration and 3D cellular protein expression was determined.

AD-01 rescued the impaired ACH-3Ps proliferation induced by DMOG (p<0.05) or Rho-6G (p<0.001). AD-01 also abrogated the TNF-α-mediated uric acid increase (p<0.001). FKBPL protein expression was reduced following DMOG treatment (p<0.05), whereas AD-01 normalised both HIF-1α (p<0.01) and FKBPL expression (p<0.001). MCM increased both HIF-1α (p<0.05) and FKBPL (p<0.01) expression, whereas AD-01 abrogated this effect (p<0.05-0.001). Suppression of FKBPL with siRNA or via MCM/DMOG, stimulated HMEC-1 migration within the chip (p<0.05-0.001).

FKBPL-based therapeutic peptide, AD-01, restored the angiogenic imbalance via FKBPL, and could be a viable treatment option for preeclampsia, with dual utility capable of rescuing trophoblast and EC dysfunction.

  1. Ghorbanpour SM, Richards C, Pienaar D, et al. A placenta-on-a-chip model to determine the regulation of FKBPL and galectin-3 in preeclampsia. Cell Mol Life Sci. 2023;80(2):44. doi:10.1007/s00018-022-04648-w
  2. Todd N, McNally R, Alqudah A, et al. Role of A Novel Angiogenesis FKBPL-CD44 Pathway in Preeclampsia Risk Stratification and Mesenchymal Stem Cell Treatment. J Clin Endocrinol Metab. 2021;106(1):26-41. doi:10.1210/clinem/dgaa403