Cellular localization of AT1 receptor mRNA and protein in normal placenta and its reduced expression in intrauterine growth restriction. Angiotensin II stimulates the release of vasorelaxants.
Cellular localization of AT1 receptor mRNA and protein in normal placenta and its reduced expression in intrauterine growth restriction. Angiotensin II stimulates the release of vasorelaxants.
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DOI：
10.1172/jci119881
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发表时间：
1998-01
期刊：
影响因子：
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通讯作者：
Xiao F. Li;M. Shams;Jun Zhu;Asud Khalig;M. Wilkes;Martin Whittle;Nicholas W. Barnes;A. Ahmed
中科院分区：
文献类型：
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作者：
Xiao F. Li;M. Shams;Jun Zhu;Asud Khalig;M. Wilkes;Martin Whittle;Nicholas W. Barnes;A. Ahmed
血管紧张素II(Ang II)是一种强有力的血管收缩和生长促进剂。使用非选择性放射性配体[125I]Ang II和亚型选择性竞争化合物的定量受体放射自显影显示，Ang II受体(AT)1和AT2受体识别位点都存在。此外，还鉴定了一个相对较少的明显非AT1/非AT2位点，这可能代表了人类胎盘中一个新的高亲和力Ang II识别位点。AT2受体拮抗剂PD123177不能竞争相应浓度的[~3H]Ang II结合，而AT1受体拮抗剂氯沙坦单相竞争所有的特异性结合，提示放射自显影鉴定的非AT1/非AT2识别位点可能是胞浆结合部位。AT1受体结合显著减少(P<；0。02)在宫内生长受限(IUGR)妊娠中。Western印迹分析证实这表明AT1受体蛋白减少。原位杂交和免疫细胞化学显示AT1受体的mRNA和蛋白在整个妊娠过程中定位于细胞滋养细胞、合体滋养细胞和绒毛外滋养细胞，以及胎盘绒毛血管内或周围。IUGR合体上AT1受体的杂交信号强度降低。血管紧张素转换酶II可诱导早孕细胞滋养层细胞迅速释放NO，此作用可被竞争性一氧化氮合酶抑制剂NG-单甲基-L-精氨酸所阻断。单独使用氯沙坦或PD123177均不能抑制Ang II诱导的NO释放，当Ang II与氯沙坦(10微米)和PD123177(10微米)共同刺激细胞时，NO的释放被显著抑制(P<；0.05)。这些观察还首次表明，滋养层细胞AT1或AT2受体之间存在串扰，IUGR胎盘AT1受体减少可能是导致这种疾病的胎盘功能不良的部分原因。
Angiotensin II (ANG II) is a potent vasoconstrictor and growth promoter. Quantitative receptor autoradiography using the nonselective radioligand [125I]ANG II and subtype-selective competing compounds demonstrated the presence of both ANG II receptor (AT)1 and AT2 receptor recognition sites. In addition, a relatively small population of apparently non-AT1/non-AT2 sites was identified that may represent a novel high affinity ANG II recognition site in human placenta. Using placental membrane preparations, the AT2 receptor antagonist PD123177 failed to compete for [3H]ANG II binding at relevant concentrations, whereas the AT1 receptor antagonist losartan competed in a monophasic manner for all the specific binding, suggesting that the non-AT1/non-AT2 recognition site identified using autoradiography may be a cytosolic binding site. AT1 receptor binding was significantly reduced (P < 0. 02) in intraeuterine growth restriction (IUGR) pregnancies. Western blot analysis confirmed this showing a reduction in AT1 receptor protein. In situ hybridization and immunocytochemistry revealed that AT1 receptor mRNA and protein were localized throughout pregnancy in the cytotrophoblast, syncytiotrophoblast, and extravillous trophoblast, as well as in or around the blood vessels of placental villi. The intensity of the hybridization signal for AT1 receptor mRNA over the syncytium was reduced in IUGR. ANG II evoked a rapid and concentration-dependent release of NO in first trimester cytotrophoblast-like cells that was abolished by the inclusion of the competitive NOS inhibitor NG-monomethyl-L-arginine. Neither losartan nor PD123177 alone significantly inhibited ANG II-evoked NO release, and when cells were stimulated with ANG II in the presence of losartan (10 microM) and PD123177 (10 microM) in combination, NO release was significantly inhibited (P < 0.05). These observations also suggest, for the first time, the existence of a cross-talk between AT1 or AT2 receptors in trophoblast and that the reduction in placental AT1 receptors in IUGR may, in part, account for poor placental function in this disorder.