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¹ Department of Biochemistry and Molecular Biology and ² Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Texas Medical School at Houston, Houston, TX, 77030

CORRESPONDENCE Yang Xia: yang.xia{at}uth.tmc.edu

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.

Abbreviations used: Ang II, angiotensin II; AT₁-AA, AT₁ receptor agonistic autoantibody; CHO, Chinese hamster ovary; IUGR, intrauterine growth restriction; TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling.

© 2009 Irani et al.
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