Linking Placental Ischemia and Hypertension in Preeclampsia

One of the most pervasive disorders of pregnancy is preeclampsia, which is defined as new-onset hypertension presenting after the 20th week of gestation and is accompanied by increasing levels of proteinuria and often edema. The overall prevalence of preeclampsia is 8% with higher incidence in specific ethnic subpopulations, notably blacks. The disorder is predominantly a complication of primiparous women, who have a 3-fold higher incidence rate than multiparous women. There are a number of known factors that convey elevated risk of developing preeclampsia, notably elevated body mass index, and a previous incidence of preeclampsia, because women who experienced preeclampsia in previous pregnancies are 7 times more likely to exhibit preeclamptic symptoms in subsequent pregnancies than those with no history of preeclampsia. It has also been shown that high body mass index can double the risk of preeclampsia, and the scale of obesity correlates directly with the increase risk of developing the disorder. Although the link between these risk factors seem logical, there are also a number of other risk factors (maternal age, induced abortions, interpregnancy interval, and socioeconomic factors) for which the links to preeclampsia are not as clear. More research is warranted into the mechanistic effect of these factors in the etiology of preeclampsia. There are currently no definitive treatment options for the resolution of preeclampsia. Available interventions are confined to magnesium sulfate for the prophylaxis of seizures and the administration of one of various antihypertensive agents, although normalization of blood pressure is not normally possible, and the disease continues to progress. Indeed, the only effective resolution of preeclampsia is delivery of the placenta, because delivery of the fetus alone is not sufficient. It is this fact that suggested the pathological origins of the development of preeclampsia. Although the underlying molecular mechanisms that lie at the root of preeclampsia are not clear, it is believed that a major causative agent is placental insufficiency resulting from inadequate remodeling of the maternal vasculature. During normal pregnancy, fetally derived cytotrophoblasts invade the maternal spiral arteries of the uterus, replace the maternal endothelium, and undergo differentiation into an endotheliallike phenotype. This causes a conversion of the highresistance, small-diameter vessels into high-capacitance, lowresistance vessels and ensures adequate delivery of maternal blood to the developing uteroplacental unit. In the preeclamptic patient, unknown errors in this carefully orchestrated scheme lead to inadequate delivery of blood to the developing uteroplacental unit and create hypoxia and chronic ischemia within the placenta. In response, the placenta produces pathogenic factors that enter the maternal bloodstream and are responsible for the clinical manifestations of the disorder. Among the factors known to be released, antiangiogenic and autoimmune/inflammatory factors have received a great deal of attention. Interestingly, recent evidence suggests that these agents have a final common pathway, activation of the endothelin 1 (ET-1) system. There are several lines of evidence that suggest a pathogenic role for ET-1 in the preeclamptic patient. A number of studies looking at circulating levels of ET-1 in preeclamptic women have generally demonstrated significantly higher levels of circulating ET-1 in the plasma of preeclamptic patients when compared with healthy controls, with some suggestion that a genetic polymorphism could play a role in the variation of ET-1 levels. However, circulating levels of ET-1 are not necessarily good indicators of ET-1 production in the tissues because of the fact that ET-1 secretion is directional, with a larger proportion of the peptide being released on the basolateral side of the endothelium, and tissue levels may not be accurately reflected in the levels of ET-1 in the circulation. Studies indicating elevations in ET-1 in preeclamptic placental cells are perhaps more telling, although this is not a universal finding. Finally, one report has indicated an increase in endothelin-converting enzyme in the circulation of preeclamptic patients compared with normal pregnant controls, suggesting a potential mechanism for enhanced local production of ET-1. These data support earlier studies demonstrating increased endothelin-converting