Unbiased Approaches for Addressing the Complexities of the Placenta’s Role in the Preeclampsia Syndrome

Introduction

It remains unclear if preeclampsia (PE) is the result of a default pathway that is activated after insults to pregnancy or involves a unique pathological process. Furthermore, it is not yet understood if the different signs of this disease can be traced to a single cause or have multiple etiologies. A two-stage model has been proposed for the manifestation of PE (and discussed in detail in Chapter 20, Chapter 5, Chapter 7, Chapter 8 ): (1) abnormal placentation (preclinical), followed by (2) maternal responses that lead to the clinical presentation of this syndrome. Lastly, PE can be classified as early onset (<34 weeks), which often has the most serious consequences (severe preeclampsia [sPE]), or late onset (>34 weeks), which has better outcomes for both fetus and mother.

The placenta is a versatile organ that “transplants” the allogeneic conceptus to the uterus and supports embryonic/fetal growth, functions that change as pregnancy advances. It is therefore reasonable to assume that its epigenetic, genetic, and proteomic landscapes will fluctuate as gestation proceeds. Unraveling these underlying changes is important as they may provide the key to understanding when and how deviations from the normal program initiate the cascade leading to PE. Therefore, parallel analyses of human placentas from normal pregnancies throughout pregnancy and those complicated by PE are an essential part of a robust study design that eliminates gestational age as a confounding variable. Another important element is the application of novel global molecular profiling technologies, which can capture the complexities inherent in human biology and pathology. We believe that application of these strategies will lead to a better understanding of the causes of PE and biomarkers for the preclinical and clinically evident stages of this syndrome.

Severe forms of PE occur early in gestation and are especially challenging to study due to the lack of available tissue. Samples of the maternal–fetal interface from uncomplicated pregnancies are not available after 24 weeks of gestation until term, when elective terminations are no longer permitted in many countries. Thus, it is impossible to obtain true control samples for studies of the severe forms of PE, which usually occur in the 24–34 week interval.

To address the lack of normal second/early third trimester tissue, our group has intensively studied placentas from noninfected preterm births (nPTBs) to determine if they are useful as gestational age-matched controls. Comparison of the maternal–fetal interface and cytotrophoblast (CTB) expression of stage-specific antigens in PE and nPTBs showed that latter samples are near normal at histological and molecular levels. We therefore concluded that nPTB placentas can be used as controls to study the effects of PE at cellular and molecular levels.

Because human tissue was unavailable to study factors that may be involved in abnormal placentation (stage 1), most studies focused on factors that play a role in maternal signs of PE (stage 2). Among other molecules, sFlt-1, ^, endoglin, and adrenomedullin have been implicated. In contrast, the mechanisms that precipitate abnormal placentation are largely unknown.

The availability of control samples allowed us to begin to uncover molecular networks that may be involved in the pathophysiology of this disease, specifically faulty placentation. Our group has carried out several transcriptomic studies at the maternal–fetal interface in control and preeclamptic placentas throughout the years. A chronological account of the results follows.

Gestational Age-dependent Changes in Gene Expression at the Maternal Fetal Interface: 14–24 Weeks Versus Term

Unexpectedly, changes in gene expression between early (14–24 weeks) and late (37–40 weeks) pregnancy showed that hundreds of alterations occur toward term, whereas few differences were found before 24 weeks, highlighting the fact that gestational age is an important variable. These findings lend insights into the networks that are required for formation of the maternal–fetal interface during the second trimester, or for the preparation of these tissues for parturition.

This analysis revealed 418 differentially regulated genes between term and mid-gestation. Based on gene ontology (GO) annotations, differentially expressed genes were involved in a variety of biological processes: transcription (24), lipid metabolism (17), formation and regulation of the extracellular matrix (10), immune effectors or modulators (21), and angiogenesis/vasculogenesis (6).