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

Irani RA, Zhang Y, Blackwell SC, Zhou CC, Ramin SM, Kellems RE, Xia Y - J. Exp. Med. (2009)

Bottom Line: Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX, 77030, USA.

ABSTRACT
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.

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Schematic of the working model of AT1 receptor–mediated apoptosis: placental and fetal consequences. AT1 receptor activation via AT1-AAs, found in the serum of preeclamptic women, leads to (1) placental damage (2) and fetal abnormalities. sEng, soluble endoglin; sFlt-1, soluble fms-like tyrosine kinase 1.
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fig7: Schematic of the working model of AT1 receptor–mediated apoptosis: placental and fetal consequences. AT1 receptor activation via AT1-AAs, found in the serum of preeclamptic women, leads to (1) placental damage (2) and fetal abnormalities. sEng, soluble endoglin; sFlt-1, soluble fms-like tyrosine kinase 1.

Mentions: In conclusion, our study demonstrates that AT1-AAs may contribute to IUGR through a direct detrimental effect by activation of AT1 receptors on multiple fetal organs, and indirectly by inducing small placentas characterized by increased trophoblast apoptosis (Fig. 7). Future work will have to delineate between the placental effects and the direct harmful action of the autoantibody on the fetus. However, there is no doubt that our studies identify AT1-AA as a detrimental factor that contributes to IUGR. Furthermore, we have shown that the blockade of excessive AT1 receptor stimulation by losartan or the 7-aa epitope peptide not only reduced the placental apoptosis observed in mouse and human placentas but also the fetal abnormalities seen in the autoantibody-injected mouse model. Thus, our work identified the detrimental role of AT1-AAs in preeclampsia-associated IUGR and revealed underlying mechanisms for this process. Selective neutralization of these autoantibodies would enhance our ability to intervene in IUGR without fetotoxicity, and suggests that targeting AT1-AAs is a potentially important therapeutic strategy for the treatment of preeclampsia and its devastating clinical fetal complications.


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

Irani RA, Zhang Y, Blackwell SC, Zhou CC, Ramin SM, Kellems RE, Xia Y - J. Exp. Med. (2009)

Schematic of the working model of AT1 receptor–mediated apoptosis: placental and fetal consequences. AT1 receptor activation via AT1-AAs, found in the serum of preeclamptic women, leads to (1) placental damage (2) and fetal abnormalities. sEng, soluble endoglin; sFlt-1, soluble fms-like tyrosine kinase 1.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2806612&req=5

fig7: Schematic of the working model of AT1 receptor–mediated apoptosis: placental and fetal consequences. AT1 receptor activation via AT1-AAs, found in the serum of preeclamptic women, leads to (1) placental damage (2) and fetal abnormalities. sEng, soluble endoglin; sFlt-1, soluble fms-like tyrosine kinase 1.
Mentions: In conclusion, our study demonstrates that AT1-AAs may contribute to IUGR through a direct detrimental effect by activation of AT1 receptors on multiple fetal organs, and indirectly by inducing small placentas characterized by increased trophoblast apoptosis (Fig. 7). Future work will have to delineate between the placental effects and the direct harmful action of the autoantibody on the fetus. However, there is no doubt that our studies identify AT1-AA as a detrimental factor that contributes to IUGR. Furthermore, we have shown that the blockade of excessive AT1 receptor stimulation by losartan or the 7-aa epitope peptide not only reduced the placental apoptosis observed in mouse and human placentas but also the fetal abnormalities seen in the autoantibody-injected mouse model. Thus, our work identified the detrimental role of AT1-AAs in preeclampsia-associated IUGR and revealed underlying mechanisms for this process. Selective neutralization of these autoantibodies would enhance our ability to intervene in IUGR without fetotoxicity, and suggests that targeting AT1-AAs is a potentially important therapeutic strategy for the treatment of preeclampsia and its devastating clinical fetal complications.

Bottom Line: Recently, emerging evidence indicates that preeclamptic women harbor AT(1) receptor agonistic autoantibodies (AT(1)-AAs) that contribute to the disease features.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX, 77030, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus