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A placenta-on-a-chip model to determine the regulation of FKBPL and galectin-3 in preeclampsia

2023; Springer Nature; Volume: 80; Issue: 2 Linguagem: Inglês

10.1007/s00018-022-04648-w

1420-9071

Sahar Ghorbanpour, Claire Richards, Dillan Pienaar, Kimberly Sesperez, Hamidreza Aboulkheyr Es, Valentina Nikolić, Nataša Karadžov Orlić, Željko Miković, Milan Stefanović, Zoran Cakic, Abdelrahim Alqudah, Louise Cole, Catherine A. Gorrie, Kristine McGrath, Mary M. Kavurma, Majid Ebrahimi Warkiani, Lana McClements,

Birth, Development, and Health

Abstract Preeclampsia is a pregnancy-specific cardiovascular disorder, involving significant maternal endothelial dysfunction. Although inappropriate placentation due to aberrant angiogenesis, inflammation and shallow trophoblast invasion are the root causes of preeclampsia, pathogenic mechanisms are poorly understood, particularly in early pregnancy. Here, we first confirm the abnormal expression of important vascular and inflammatory proteins, FK506-binding protein-like (FKBPL) and galectin-3 (Gal-3), in human plasma and placental tissues from women with preeclampsia and normotensive controls. We then employ a three-dimensional microfluidic placental model incorporating human umbilical vein endothelial cells (HUVECs) and a first trimester trophoblast cell line (ACH-3P) to investigate FKBPL and Gal-3 signaling in inflammatory conditions. In human samples, both circulating ( n = 17 controls; n = 30 preeclampsia) and placental ( n ≥ 6) FKBPL and Gal-3 levels were increased in preeclampsia compared to controls (plasma: FKBPL, p < 0.0001; Gal-3, p < 0.01; placenta: FKBPL, p < 0.05; Gal-3, p < 0.01), indicative of vascular dysfunction in preeclampsia. In our placenta-on-a-chip model, we show that endothelial cells are critical for trophoblast-mediated migration and that trophoblasts effectively remodel endothelial vascular networks. Inflammatory cytokine tumour necrosis factor-α (10 ng/mL) modulates both FKBPL and Gal-3 signaling in conjunction with trophoblast migration and impairs vascular network formation ( p < 0.005). Our placenta-on-a-chip recapitulates aspects of inappropriate placental development and vascular dysfunction in preeclampsia.