Defective Trophoblast Differentiation, Endothelial Dysfunction, and Immune Dysregulation in Preeclampsia Coalesce on a Placental VGLL3-Centered Gene Network
Abstract
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.
Article Details
Authors (25)
Olesya Plazyo
Laura B. Chopp
Departments 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.
Rishyanth Peela
Departments 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.
Kelly Young
Haihan Zhang
School of Chemical Engineering and Technology
Rachael Bogle
Ashley Hesson
Obstetrics(and)Gynecology (A.H., E.S.L.), University of Michigan, Ann Arbor, MI.
Elizabeth S. Langen
Ingrid L. Bergin
Li-Jyun Syu
Departments 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.
Jake Erba
Departments 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.
Joseph Kirma
Poulami Dey
Departments 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.
Lin Zhang
Mrinal K. Sarkar
William R. Swindell
Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX (W.R.S.).
Katherine A. Gallagher
Nicole L. Ward
Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN (N.L.W.).
Kanakadurga Singer
Pediatrics (K.S.), University of Michigan, Ann Arbor, MI.
J. Michelle Kahlenberg
Allison C. Billi
Andrzej A. Dlugosz
Santhi K. Ganesh
Internal Medicine (J.M.K., S.K.G., J.E.G.), University of Michigan, Ann Arbor, MI.
Lam C. Tsoi
Johann E. Gudjonsson