Inactivation of Yes-Associated Protein Mediates Trophoblast Dysfunction: A New Mechanism of Pregnancy Loss Associated with Anti-Phospholipid Antibodies?

Abstract

Pregnancy morbidity induced by anti-phospholipid antibodies (aPL+/PM+) is mainly thought to arise from placental abnormalities. We attempted to investigate the effect of aPL on the activity of Yes-associated protein (YAP) in the trophoblast and how YAP regulated human trophoblasts function. Thus, HTR-8 cells were treated with IgG purified from aPL+/PM+ women or normal controls. We found that aPL+/PM+ IgG impacted YAP activity via abrogating YAP expression. Further investigation of the anti-β2GPI-IgG/β2GPI complex showed an inhibition of nuclear YAP level and translocation in a dose-dependent manner, which might be rescued by progesterone in HTR-8 cells. YAP overexpression or knockdown HTR-8 cells were established for the evaluation of cell function and related gene expression in vitro. Loss of YAP arrested cell cycles in the G2/M phase, accelerated cell apoptosis by increasing the ratio of Bax/Bcl2, and disrupted MMP2/9-mediated cell migration and angiogenesis tube formation by VEGF. These findings support a new mechanism of PM associated with aPL through which YAP inactivation induced by aPL perturbs the trophoblast cell cycle, apoptosis, migration, and angiogenesis, finally developing into pregnancy failure.

Trophoblast Cell Function in the Antiphospholipid Syndrome

“…Namely, it was detected that aPL treatment decreased YAP protein levels in HTR-8/SVneo cells [101]. YAP downregulation increased apoptosis, inhibited migration, invasion and tube formation ability of HTR-8/SVneo cells [101][102][103]. Previous studies of early implantation and trophoblast development showed that inhibition of YAP reduced endometrial attachment, outgrowth, and trophoblast gene expressions of human embryonic stem cell-derived trophoblastic spheroids [104].…”

“…Recently, Yes-associated protein (YAP), the transcription co-activator of the Hippo signaling pathway, was proposed to act as key effector molecule which links aPL-induced upstream intracellular signals and alteration of different trophoblast functions [101]. Namely, it was detected that aPL treatment decreased YAP protein levels in HTR-8/SVneo cells [101]. YAP downregulation increased apoptosis, inhibited migration, invasion and tube formation ability of HTR-8/SVneo cells [101][102][103].…”