FKBPL signalling is critical for placental and foetal survival — ASN Events
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  3. FKBPL signalling is critical for placental and foetal survival

FKBPL signalling is critical for placental and foetal survival (#515)

Suchitha Rao 1 , Fatemeh Heidari 1 , Kristine McGrath 1 , Lana McClements 1 2
  1. University of Technology Sydney, Lidcombe, NSW, Australia
  2. Faculty of Science, Institute for Biomedical Materials and Devices, Sydney, NSW, Australia

Background

Placental dysfunction, altered placental steroid hormone production, and angiogenic imbalance are key underlying mechanisms of preeclampsia and foetal growth restriction (1). Previous research showed that the anti-angiogenic protein, FKBPL, regulates steroid receptor signalling in the context of hormone-positive cancers (2-4). We hypothesise that FKBPL plays a critical role in placental and foetal development by regulating steroid receptor signalling, and that FKBPL dysregulation is associated with preeclampsia.

Methods

Placental tissue from wild-type (WT) or Fkbpl+/- mice induced to overexpress sFLT-1 using a non-viral gene delivery system, RALA, (n ≥ 3), were utilised. Pregnant mice were either subjected to exercise, treated with metformin (300mg/kg) or AD-01– an FKBPL peptide mimetic (0.003mg/kg), or administered human FLT-1 (5µg). On gestational day 18, mice were sacrificed and placentas and embryos weighed. To quantify changes in the size of functional zones, whole placenta, labyrinth zone (gas and nutrient transfer [LZ]), and junctional zone (hormone secretion, vascular remodelling [JZ]) areas were subjected to H&E staining and quantified using QuPath.

Results

sFlt-1 significantly reduced embryo weight in WT and Fkbpl+/- mice compared to vehicle control (p < 0.0001), but placental weight or structural changes were not observed in either genotype. In WT mice, exercise significantly reduced placental LZ:JZ (p = 0.0264) despite no change in embryo and placental weight. Exercise restored embryo weight in Fkbpl⁺/⁻ mice (p < 0.0001), without impacting placental weight or structure. Metformin significantly lowered LZ:JZ (p = 0.0351) in WT mice only without affecting embryo or placental wight. While AD-01 showed no effect, hFlt-1 restored embryo weight in both genotypes (p < 0.0001) without altering placental weight or structure.

Conclusion

Although sFlt-1 overexpression reduced embryo weight, whereas hFlt-1 treatment restored it, neither affected placental efficiency suggesting an alternative mechanism. Interestingly, exercise impacted placenta and embryo in a genotype specific manner.

 

  1. Lan KC, Lai YJ, Cheng HH, Tsai NC, Su YT, Tsai CC, et al. Levels of sex steroid hormones and their receptors in women with preeclampsia. Reprod Biol Endocrinol. 2020;18(1):12.
  2. McKeen HD, Byrne C, Jithesh PV, Donley C, Valentine A, Yakkundi A, et al. Fkbpl regulates estrogen receptor signaling and determines response to endocrine therapy. Cancer Res. 2010;70(3):1090-100.
  3. McKeen HD, McAlpine K, Valentine A, Quinn DJ, McClelland K, Byrne C, et al. A novel fk506-like binding protein interacts with the glucocorticoid receptor and regulates steroid receptor signaling. Endocrinology. 2008;149(11):5724-34.
  4. Sunnotel O, Hiripi L, Lagan K, McDaid JR, De Leon JM, Miyagawa Y, et al. Alterations in the steroid hormone receptor co-chaperone fkbpl are associated with male infertility: A case-control study. Reprod Biol Endocrinol. 2010;8:22.