Hypertensive disorders of pregnancy-chronic hypertension, gestational hypertension, and preeclampsia-are uniquely challenging as the pathology and its therapeutic management simultaneously affect mother and fetus, sometimes putting their well-being at odds with each other. Preeclampsia, in particular, is one of the most feared complications of pregnancy. Often presenting as new-onset hypertension and proteinuria during the third trimester, preeclampsia can progress rapidly to serious complications, including death of both mother and fetus. While the cause of preeclampsia is still debated, clinical and pathological studies suggest that the placenta is central to the pathogenesis of this syndrome. In this review, we will discuss the current evidence for the role of abnormal placentation and the role of placental factors such as the antiangiogenic factor, sFLT1 (soluble fms-like tyrosine kinase 1) in the pathogenesis of the maternal syndrome of preeclampsia. We will discuss angiogenic biomarker assays for disease-risk stratification and for the development of therapeutic strategies targeting the angiogenic pathway. Finally, we will review the substantial long-term cardiovascular and metabolic risks to mothers and children associated with gestational hypertensive disorders, in particular, preterm preeclampsia, and the need for an increased focus on interventional studies during the asymptomatic phase to delay the onset of cardiovascular disease in women.

Preeclampsia: Pathophysiology, Challenges, and Perspectives

Preeclampsia is a systemic syndrome that occurs in 3 to 5% of pregnant women and classically manifests as new-onset hypertension and proteinuria after 20 weeks of gestation. Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality. The only known cure is delivery of the placenta. Recent discoveries, however, have led to important advances in understanding the pathogenesis of the condition. Placental antiangiogenic factors are upregulated and disrupt the maternal endothelium. This change in the normal angiogenic balance toward an antiangiogenic state can result in hypertension, proteinuria, glomerular endotheliosis, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and cerebral edema—the clinical signs of preeclampsia and eclampsia. The regulation of these antiangiogenic factors in the placenta is unknown. The recent discoveries of upregulated antiangiogenic factors provide promise for future testing to predict and diagnose preeclampsia as well as therapeutic ta...

Pathogenesis of Preeclampsia

The placenta is the principal metabolic, respiratory, excretory, and endocrine organ for the first 9 months of fetal life. Its role in fetal and maternal physiology is remarkably diverse. Because of the central role that the placenta has in fetal and maternal physiology and development, the possibility that variation in placental gene expression patterns might be linked to important abnormalities in maternal or fetal health, or even variations in later life, warrants investigation. As an initial step, we used DNA microarrays to analyze gene expression patterns in 72 samples of amnion, chorion, umbilical cord, and sections of villus parenchyma from 19 human placentas from successful full-term pregnancies. The umbilical cord, chorion, amnion, and villus parenchyma samples were readily distinguished by differences in their global gene-expression patterns, many of which seemed to be related to physiology and histology. Differentially expressed genes have roles that include placental trophoblast secretion, signal transduction, metabolism, immune regulation, cell adhesion, and structure. We found interindividual differences in expression patterns in villus parenchyma and systematic differences between the maternal, fetal, and intermediate layers. A group of genes that was expressed in both the maternal and fetal villus parenchyma sections of placenta included genes that may be associated with preeclampsia. We identified sets of genes whose expression in placenta was significantly correlated with the sex of the fetus. This study provides a rich and diverse picture of the molecular variation in the placenta from healthy pregnancies.

https://www.pnas.org/content/pnas/103/14/5478.full.pdf

Gene expression patterns in human placenta

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation.

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Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

Background: Oxygen plays a central role in human placental pathologies including preeclampsia, a leading cause of fetal and maternal death and morbidity. Insufficient uteroplacental oxygenation in preeclampsia is believed to be responsible for the molecular events leading to the clinical manifestations of this disease. Design: Using high-throughput functional genomics, we determined the global gene expression profiles of placentae from high altitude pregnancies, a natural in vivo model of chronic hypoxia, as well as that of first-trimester explants under 3 and 20% oxygen, an in vitro organ culture model. We next compared the genomic profile from these two models with that obtained from pregnancies complicated by preeclampsia. Microarray data were analyzed using the binary tree-structured vector quantization algorithm, which generates global gene expression maps. Results: Our results highlight a striking global gene expression similarity between 3% O2-treated explants, high-altitude placentae, and importan...

Francesca Ietta

Papers

Molecular Evidence of Placental Hypoxia in Preeclampsia