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 AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features. However, the exact role of AT(1)-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 AT(1) receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT(1)-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT(1)-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 AT(1)-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 AT(1)-AA-induced placental damage. Our findings highlight AT(1)-AAs as important therapeutic targets.
Irani
Roxanna A
RA
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX, 77030, USA.
Zhang
Yujin
Y
Blackwell
Sean C
SC
Zhou
Cissy Chenyi
CC
Ramin
Susan M
SM
Kellems
Rodney E
RE
Xia
Yang
Y
D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D008431:Maternal-Fetal Exchange / Q000276:immunology*; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D011225:Pre-Eclampsia / Q000097:blood / Q000188:drug therapy / Q000276:immunology*; D011247:Pregnancy; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists* / Q000276:immunology*; D014327:Trophoblasts / Q000276:immunology / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D001323:Autoantibodies; D010455:Peptides; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan