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Publications

Journal Article Preprint Epublish 1 citation

PubMed: 40502186 DOI: 10.1101/2025.05.30.657097

VGLL3-centered network connects placental, vascular, and immune defects in preeclampsia.

bioRxiv

Authors: Olesya Plazyo, Laura B Chopp, Rishyanth Peela, Kelly Young, Haihan Zhang, Rachael Bogle, Ashley Hesson, Elizabeth S Langen, Ingrid L Bergin, Li-Jyun Syu, Jake Erba, Joseph Kirma, Poulami Dey, Lin Zhang, Mrinal K Sarkar, William R Swindell, Katherine A Gallagher, Nicole L Ward, Kanakadurga Singer, J Michelle Kahlenberg, Allison C Billi, Andrzej A Dlugosz, Santhi K Ganesh, Lam C Tsoi, Johann E Gudjonsson

Affiliations

  • Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
  • Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • Department of Surgery, Division of Vascular Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
  • Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Division of Pediatric Endocrinology, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
  • Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.

Abstract

Preeclampsia affects approximately 1 in 10 pregnancies, leading to severe complications and long-term health risks for both mother and offspring. While the etiology remains unclear, preeclampsia has been linked to both autoimmunity and the timing of menarche. Through human single-cell and spatial analyses, coupled with in vitro, in vivo, and ex vivo models, we demonstrate that VGLL3, a transcription co-regulator in the Hippo pathway, is upregulated in preeclamptic placentas. VGLL3 promotes immune activation, impairs trophoblast differentiation, and induces endothelial dysfunction, all of which contribute to pregnancy-related hypertension, fetal growth restriction, and offspring mortality. Our data reveal that VGLL3 acts upstream of preeclampsia-associated processes, including the production of sFLT1, a key biomarker of the disease. Notably, targeting VGLL3-either by genetic deletion in mouse placentas or through therapeutic inhibition in human placentas-protects against preeclampsia and alleviates disease pathology. These findings position VGLL3 as a promising novel therapeutic target for preeclampsia.

MeSH

Pregnancy, Pre-Eclampsia, Therapeutics, Placenta