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Defective Trophoblast Differentiation, Endothelial Dysfunction, and Immune Dysregulation in Preeclampsia Coalesce on
Olesya Plazyo1, Laura B Chopp1, Rishyanth Peela1
1Departments of Dermatology (O.P., L.B.C., R.P., K.Y., H.Z., R.B., L.-J.S., J.E., J.K., P.D., L.Z., M.K.S., J.M.K., A.C.B., A.A.D., L.C.T., J.E.G.), University of Michigan, Ann Arbor, MI.
Insights
Preeclampsia, a pregnancy complication, is linked to the VGLL3 protein. Targeting VGLL3 in placental cells offers a potential new treatment for preeclampsia, improving maternal and infant outcomes.
Area of Science:
- Reproductive biology
- Molecular genetics
- Immunology
Background:
- Preeclampsia affects 1 in 10 pregnancies, causing severe maternal and offspring complications.
- The exact causes of preeclampsia are unknown but may involve autoimmunity and menarche timing.
Purpose of the Study:
- To investigate the role of VGLL3 in preeclampsia pathogenesis.
- To explore VGLL3 as a potential therapeutic target for preeclampsia.
Main Methods:
- Human single-cell and spatial analyses.
- In vitro, in vivo, and ex vivo models.
- Analysis of VGLL3 expression and function in placental tissue.
Main Results:
- VGLL3 is upregulated in preeclamptic placentas.
- VGLL3 promotes immune activation, impairs trophoblast differentiation, and causes endothelial dysfunction.
- VGLL3 targets processes including sFLT1 production, a preeclampsia biomarker.
- Genetic deletion or therapeutic inhibition of VGLL3 in placental models protected against preeclampsia pathology.
Conclusions:
- VGLL3 plays a critical role in preeclampsia development.
- Targeting VGLL3 presents a promising therapeutic strategy for preeclampsia.
Background:
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.
Methods:
Through human single-cell and spatial analyses, coupled with in vitro, in vivo, and ex vivo models, we demonstrate that VGLL3 (Vestigial-like family member 3), a transcription coregulator in the Hippo pathway, is upregulated in preeclamptic placentas.
Results:
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 (soluble fms-like tyrosine kinase 1), 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.
Conclusions:
These findings position VGLL3 as a promising novel therapeutic target for preeclampsia.
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