Pregnancy-associated diamine oxidase originates from extravillous trophoblasts and is decreased in early-onset preeclampsia

Philipp Velicky,Thomas Boehm,Tamara Weiss,Christian Fiala,Jürgen Pollheimer,Birgit Reiter,David E Cantonwine,Karin Windsperger,Martin Knöfler,Sigrid Vondra,Karin Petroczi,Robin Ristl,Bernd Jilma,Sabine Dekan,Thomas F Mcelrath,Sophie Pils

doi:10.1038/s41598-018-24652-0

Abstract

Human extravillous trophoblast (EVT) invasion of the pregnant uterus constitutes a pivotal event for the establishment of the maternal-fetal interface. Compromised EVT function manifesting in inadequate arterial remodeling is associated with the severe pregnancy disorder early-onset preeclampsia (eoPE). Recent studies suggest that EVTs invade the entire uterine vasculature including arteries, veins and lymphatics in the first trimester of pregnancy. We therefore hypothesized that EVT-derived factors accumulate in the circulation of pregnant women early in gestation and may serve to predict eoPE. In contrast to published literature, we demonstrate that placenta-associated diamine oxidase (DAO) is not expressed by maternal decidual cells but solely by EVTs, especially when in close proximity to decidual vessels. Cultures of primary EVTs express and secret large amounts of bioactive DAO. ELISA measurements indicate a pregnancy-specific rise in maternal DAO plasma levels around gestational week (GW) 7 coinciding with vascular invasion of EVTs. Strikingly, DAO levels from eoPE cases were significantly lower (40%) compared to controls in the first trimester of pregnancy but revealed no difference at mid gestation. Furthermore, DAO-containing pregnancy plasma rapidly inactivates pathophysiologically relevant histamine levels. This study represents the first proof of concept suggesting EVT-specific signatures as diagnostic targets for the prediction of eoPE.

Highlights

Human extravillous trophoblast (EVT) invasion of the pregnant uterus constitutes a pivotal event for the establishment of the maternal-fetal interface
diamine oxidase (DAO) protein expression is restricted to a subset of EVTs and the percentage of DAO+ EVTs is more than doubled when they are in proximity to decidual vessels
These findings may be interpreted in different ways: - EVTs-specific DAO expression could be induced by maternal signals depending on the localization within the maternal uterus; or - DAO+ EVTs may represent a unique trophoblast subtype destined to target the decidual vasculature

Summary

Introduction

Human extravillous trophoblast (EVT) invasion of the pregnant uterus constitutes a pivotal event for the establishment of the maternal-fetal interface. Upon attachment to the pregnant uterus (decidua) CTB progenitors at the proximal end of placental cell columns give rise to so-called extravillous trophoblasts (EVTs)[2]. This trophoblast subtype gains an invasive, mesenchymal phenotype and infiltrates the maternal uterus as deep as the inner third of the myometrium[3]. Low DAO activity in the first trimester of pregnancy has been associated with an increased risk of fetal death by about sixteen fold, suggesting a pivotal role for DAO during human pregnancy[21]. We investigated the uteroplacental expression pattern of DAO, its capacity to inactivate histamine in the serum of pregnant women and its potential as biomarker for eoPE

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