Potential Roles of Angiotensin Receptor-Activating Autoantibody in the Pathophysiology of Preeclampsia

Abstract

Preeclampsia affects ≈7% of first pregnancies and is one of the leading causes of maternal and neonatal mortality and morbidity in the United States and the world.1–3 The clinical hallmarks of the disorder include hypertension, proteinuria, hypercoagulability, edema, and placental abnormalities. In advanced stages, clinical symptoms include cerebral edema, renal failure, and the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. The clinical management of preeclampsia is hampered by the lack of reliable diagnostic tests and effective therapy for the disorder. In some cases, termination of pregnancy is the only available option to prevent further deterioration of the fetus and mother. Fifteen percent of all preterm births are indicated early deliveries for preeclampsia.3 The resulting preterm births and the associated increased infant morbidity and mortality are especially disheartening consequences of preeclampsia. Despite being one of the leading causes of maternal death and a major contributor to maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of preeclampsia are poorly understood. Roberts and colleagues4,5 were among the first to propose that alterations in endothelial cell function by activating agents produced by the placenta initiate the clinical syndromes of preeclampsia. Circulating factors, such as inflammatory cytokines, endothelin, and soluble vascular endothelial growth factor receptor termed soluble fms-like tyrosine kinase-1 (sFlt-1), are elevated in preeclamptic women and are proposed to be important links between placental ischemia and endothelial dysfunction.5–9 In particular, recent studies have shown that preeclampsia is associated with the presence of maternal autoantibodies capable of binding to and activating the angiotensin (Ang) receptor type-1 (AT1).10–15 AT1 receptor agonistic antibodies, herein termed AT1-AA, are rarely seen in normotensive pregnant women.10,11 Since the initial discovery of these autoantibodies, considerable evidence supporting a pathophysiological role of AT1-AA in preeclampsia has …