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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.

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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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Mouse placentas demonstrate increased apoptosis caused by AT1 receptor activation. The placentas of AT1-AA–injected pregnant mice have increased apoptosis. (A) TUNEL-stained mouse placental sections demonstrate increased apoptosis in the labyrinth zone of mice injected with IgG from preeclamptic women as compared with normotensive IgG-injected mice (green, TUNEL+; blue, DAPI nuclear stain). Bars, 500 µm. (B) This qualitative increase in apoptosis is quantified and corroborated with an increased apoptotic index (percentage of TUNEL-/DAPI-positive cells) as measured in the same mouse placental sections (n = 12 placentas for each variable collected over four independent experiments). (C and D) Western blot analysis of mouse placentas indicates that AT1 receptor activation leads to increased Bax (C) and decreased Bcl-2 (D; n = 6 for each variable collected over four independent experiments). Mice coinjected with IgG from preeclamptic women and either losartan or 7-aa epitope peptide have placentas that demonstrate less apoptotic features. Data are expressed as means ± SEM. *, P < 0.05 versus normotensive IgG treatment; **, P < 0.05 versus preeclamptic IgG treatment. NT, normotensive; PE, preeclampsia.
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fig4: Mouse placentas demonstrate increased apoptosis caused by AT1 receptor activation. The placentas of AT1-AA–injected pregnant mice have increased apoptosis. (A) TUNEL-stained mouse placental sections demonstrate increased apoptosis in the labyrinth zone of mice injected with IgG from preeclamptic women as compared with normotensive IgG-injected mice (green, TUNEL+; blue, DAPI nuclear stain). Bars, 500 µm. (B) This qualitative increase in apoptosis is quantified and corroborated with an increased apoptotic index (percentage of TUNEL-/DAPI-positive cells) as measured in the same mouse placental sections (n = 12 placentas for each variable collected over four independent experiments). (C and D) Western blot analysis of mouse placentas indicates that AT1 receptor activation leads to increased Bax (C) and decreased Bcl-2 (D; n = 6 for each variable collected over four independent experiments). Mice coinjected with IgG from preeclamptic women and either losartan or 7-aa epitope peptide have placentas that demonstrate less apoptotic features. Data are expressed as means ± SEM. *, P < 0.05 versus normotensive IgG treatment; **, P < 0.05 versus preeclamptic IgG treatment. NT, normotensive; PE, preeclampsia.

Mentions: Placental health is vital for normal fetal development. In an effort to determine whether an impaired placenta is another potential underlying mechanism for AT1-AA–induced IUGR, we evaluated the size and morphology of placentas in the autoantibody-injected mouse model of preeclampsia. The results (Fig. 3) show that placentas from pregnant mice injected with AT1-AAs were significantly smaller (0.0939 ± 0.008 g) than placentas from mice injected with a comparable amount of total IgG from normotensive pregnant women (0.1039 ± 0.014 g). In addition, coinjection of AT1-AAs with either losartan or 7-aa epitope peptide restored placental size to 0.0991 ± 0.009 g and 0.105 ± 0.023 g, respectively. To determine whether increased apoptosis is a potential cause of the small placentas observed in AT1-AA–injected pregnant mice, we performed terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) staining for apoptotic cells and found that the reduction in placental size was accompanied by an increase in apoptosis evident in the labyrinth zone of placentas from mice injected with AT1-AAs (Fig. 4, A and B). In addition, Bax, a proapoptotic marker, was increased, and Bcl-2, an antiapoptotic marker, was decreased as determined by Western blot analysis of mouse placenta protein extracts (Fig. 4, C and D). Coinjection of AT1-AAs with losartan or 7-aa epitope peptide significantly inhibited these features. Therefore, increased apoptosis may contribute to the reduction in placental size in pregnant mice injected with AT1-AAs. These findings also suggest that an impaired placenta may indirectly be another underlying mechanism of AT1-AA–induced IUGR in pregnant mice.


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)

Mouse placentas demonstrate increased apoptosis caused by AT1 receptor activation. The placentas of AT1-AA–injected pregnant mice have increased apoptosis. (A) TUNEL-stained mouse placental sections demonstrate increased apoptosis in the labyrinth zone of mice injected with IgG from preeclamptic women as compared with normotensive IgG-injected mice (green, TUNEL+; blue, DAPI nuclear stain). Bars, 500 µm. (B) This qualitative increase in apoptosis is quantified and corroborated with an increased apoptotic index (percentage of TUNEL-/DAPI-positive cells) as measured in the same mouse placental sections (n = 12 placentas for each variable collected over four independent experiments). (C and D) Western blot analysis of mouse placentas indicates that AT1 receptor activation leads to increased Bax (C) and decreased Bcl-2 (D; n = 6 for each variable collected over four independent experiments). Mice coinjected with IgG from preeclamptic women and either losartan or 7-aa epitope peptide have placentas that demonstrate less apoptotic features. Data are expressed as means ± SEM. *, P < 0.05 versus normotensive IgG treatment; **, P < 0.05 versus preeclamptic IgG treatment. NT, normotensive; PE, preeclampsia.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2806612&req=5

fig4: Mouse placentas demonstrate increased apoptosis caused by AT1 receptor activation. The placentas of AT1-AA–injected pregnant mice have increased apoptosis. (A) TUNEL-stained mouse placental sections demonstrate increased apoptosis in the labyrinth zone of mice injected with IgG from preeclamptic women as compared with normotensive IgG-injected mice (green, TUNEL+; blue, DAPI nuclear stain). Bars, 500 µm. (B) This qualitative increase in apoptosis is quantified and corroborated with an increased apoptotic index (percentage of TUNEL-/DAPI-positive cells) as measured in the same mouse placental sections (n = 12 placentas for each variable collected over four independent experiments). (C and D) Western blot analysis of mouse placentas indicates that AT1 receptor activation leads to increased Bax (C) and decreased Bcl-2 (D; n = 6 for each variable collected over four independent experiments). Mice coinjected with IgG from preeclamptic women and either losartan or 7-aa epitope peptide have placentas that demonstrate less apoptotic features. Data are expressed as means ± SEM. *, P < 0.05 versus normotensive IgG treatment; **, P < 0.05 versus preeclamptic IgG treatment. NT, normotensive; PE, preeclampsia.
Mentions: Placental health is vital for normal fetal development. In an effort to determine whether an impaired placenta is another potential underlying mechanism for AT1-AA–induced IUGR, we evaluated the size and morphology of placentas in the autoantibody-injected mouse model of preeclampsia. The results (Fig. 3) show that placentas from pregnant mice injected with AT1-AAs were significantly smaller (0.0939 ± 0.008 g) than placentas from mice injected with a comparable amount of total IgG from normotensive pregnant women (0.1039 ± 0.014 g). In addition, coinjection of AT1-AAs with either losartan or 7-aa epitope peptide restored placental size to 0.0991 ± 0.009 g and 0.105 ± 0.023 g, respectively. To determine whether increased apoptosis is a potential cause of the small placentas observed in AT1-AA–injected pregnant mice, we performed terminal deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL) staining for apoptotic cells and found that the reduction in placental size was accompanied by an increase in apoptosis evident in the labyrinth zone of placentas from mice injected with AT1-AAs (Fig. 4, A and B). In addition, Bax, a proapoptotic marker, was increased, and Bcl-2, an antiapoptotic marker, was decreased as determined by Western blot analysis of mouse placenta protein extracts (Fig. 4, C and D). Coinjection of AT1-AAs with losartan or 7-aa epitope peptide significantly inhibited these features. Therefore, increased apoptosis may contribute to the reduction in placental size in pregnant mice injected with AT1-AAs. These findings also suggest that an impaired placenta may indirectly be another underlying mechanism of AT1-AA–induced IUGR in pregnant mice.

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