The detrimental role of angiotensin receptor agonistic autoantibodies in intrauterine growth restriction seen in preeclampsia

Growth-restricted fetuses are at risk for a variety of lifelong medical conditions. Preeclampsia, a life-threatening hypertensive disorder of pregnancy, is associated with fetuses who suffer from intrauterine growth restriction (IUGR). Recently, emerging evidence indicates that preeclamptic women harbor AT₁ receptor agonistic autoantibodies (AT₁-AAs) that contribute to the disease features. However, the exact role of AT₁-AAs in IUGR and the underlying mechanisms have not been identified. We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT₁ receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT₁-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT₁-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT₁-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta and entering fetal circulation, and indirectly through AT₁-AA–induced placental damage. Our findings highlight AT₁-AAs as important therapeutic targets.Intrauterine growth restriction (IUGR) is generally defined as fetal growth in <10th percentile for gestational age (Cetin et al., 2004) and affects 7–15% of pregnancies (Alexander et al., 2003; Cetin and Alvino, 2009). Growth-restricted fetuses have a higher incidence of mortality and morbidity than fetuses of normal growth, and are at increased risk for future development of metabolic disorders such as hypertension, coronary heart disease, dyslipidemia, obesity, impaired glucose tolerance, type 2 diabetes mellitus, and many other diseases (Barker, 1998; Godfrey and Barker, 2000; Baum et al., 2003; Hales and Ozanne, 2003). Most cases of IUGR, particularly those with significant recurrent risks, are often considered the result of ischemic placental disease (Roberts and Post, 2008; Cetin and Alvino, 2009). However, the factors contributing to placental distress and IUGR remain largely unknown.IUGR and ischemic placentas are frequently associated with a serious hypertensive disorder of pregnancy, preeclampsia (Kaufmann et al., 2003). When IUGR is observed, the preeclamptic mothers often have a poorly developed placenta characterized by shallow trophoblast invasion and inadequate spiral artery remodeling (Zhou et al., 1997a; Zhou et al., 1997b). Therefore, preeclampsia represents an appropriate disease model to investigate the molecular basis of placental damage and IUGR. Alterations in both the immune system and the renin–angiotensin system (RAS) are believed to contribute to the pathophysiology of preeclampsia (Redman and Sargent, 2005; Shah, 2006; Saito et al., 2007, Irani and Xia, 2008). Recently, these two mechanisms have been merged with reports that preeclamptic women harbor autoantibodies that activate the major angiotensin II (Ang II) receptor, AT₁, and are hence termed AT₁ receptor agonistic autoantibodies (AT₁-AAs; Wallukat et al., 1999). Many features of preeclampsia can be explained by the ability of these autoantibodies to activate AT₁ receptor on a variety of cell types (Xia et al., 2003; Thway et al., 2004; Bobst et al., 2005; Zhou et al., 2008a). We have recently shown that the introduction of these autoantibodies into pregnant mice resulted in hypertension, proteinuria, and other key features of preeclampsia (Zhou et al., 2008b). The autoantibody-induced features of preeclampsia were prevented by coinjection with losartan, an AT₁ receptor antagonist, or a 7-aa epitope peptide that blocks autoantibody-induced AT₁ receptor activation. These in vivo studies provide the first direct evidence of the pathophysiological role of AT₁-AAs in the maternal features of preeclampsia, and suggest that this animal model will be an extremely valuable investigative tool to analyze the underlying pathogenic mechanisms of various abnormalities associated with the disease. Thus, we used this animal model of preeclampsia to address the exact contributory role of AT₁-AAs in IUGR and its underlying mechanisms.In this paper, we show that AT₁-AAs exist in the cord blood of women with preeclampsia and in the fetal circulation of autoantibody-injected pregnant mice. We also observed that the autoantibody-induced preeclamptic model results in IUGR with impaired multiple organ development. Our findings indicate that these pathogenic autoantibodies enter the fetal circulation, where they may have a direct detrimental effect on fetal growth and maturation. Additionally, we found that AT₁-AAs impair placental development, resulting in organs characterized by increased apoptosis. These results were corroborated with similar findings in human placental villous explants and in cultured human trophoblast cells exposed to the autoantibody. These studies demonstrate that an abnormal placenta may be another underlying mechanism for AT₁-AA–induced IUGR. Finally, autoantibody-induced fetal growth restriction and placental apoptosis were largely corrected by coinjection with either losartan or an antibody-neutralizing 7-aa epitope peptide, indicating that autoantibody-mediated AT₁ receptor activation was required. Overall, our studies reveal the detrimental role of AT₁-AAs in IUGR and reveal two underlying mechanisms for this process. These novel findings point to possible adverse effects of AT₁-AAs on babies born to mothers with preeclampsia and identify these autoantibodies as potentially important therapeutic targets.