MT-MMPs in pre-eclamptic placenta: Relationship to soluble endoglin production
MT-MMPs in pre-eclamptic placenta: Relationship to soluble endoglin production
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DOI：
10.1016/j.placenta.2012.11.034
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发表时间：
2013-02-01
期刊：
影响因子：
3.8
通讯作者：
Tong, S.
中科院分区：
文献类型：
--
作者：
Kaitu'u-Lino, T. J.;Tuohey, L.;Tong, S.
简介：先兆子痫是一种严重的妊娠并发症，其特征是严重的内皮功能障碍，导致高血压、蛋白尿和母体终末器官损伤。可溶性内皮因子是胎盘释放的一种抗血管生成因子，与严重的先兆子痫有关。我们最近报道 MMP-14 能够裂解内皮糖蛋白，从胎盘中释放可溶性内皮糖蛋白，但抑制研究仅部分抑制了产生。为此，我们试图鉴定介导内皮糖蛋白从胎盘脱落的其他蛋白酶。 MMP-14 是六膜型 (MT-) MMP 之一，是 MMP 超家族的一个亚家族，因其膜结合性而得名。 MMP-15 在系统发育上是与 MMP-14 最接近的 MMP，但其抑制对胎盘中可溶性内皮糖蛋白的产生没有影响。方法：在这里，我们旨在表征严重早发性先兆子痫胎盘中剩余的四种 MT-MMP（MMP-16、-17、-24 和 -25），并评估它们对可溶性内皮糖蛋白产生的相对贡献。结果：免疫定位研究揭示MMP-16、-24和-25定位于合体滋养层，与内皮糖蛋白位于同一位点，而MMP-17主要定位于胎儿血管和下面的基质。与妊娠匹配的早产对照相比，先兆子痫胎盘中的 MMP-17 蛋白显着上调 (p < 0.05)，而 MMP-25 mRNA 显着下调 (p < 0.05)。合胞化 BeWo 细胞中 MMP-16、-17、-24 和 -25 的 siRNA 敲除不会改变体外可溶性内皮糖蛋白的产生。结论：这是第一项表征 MT-MMP 蛋白在人胎盘中定位的研究，并表明 MMP-14 是唯一有助于先兆子痫产生可溶性内皮糖蛋白的 MT-MMP。 (C) 2012 Elsevier Ltd. 保留所有权利。
Introduction: Pre-eclampsia is a serious complication of pregnancy, characterized by severe endothelial dysfunction resulting in hypertension, proteinuria and maternal end-organ damage. Soluble endoglin is an anti-angiogenic factor released from placenta that has been linked to severe pre-eclampsia. We recently reported MMP-14 is capable of cleaving endoglin to release soluble endoglin from placenta, however inhibition studies only partially repressed production. To this end we have sought to identify other proteases that mediate endoglin shedding from placenta. MMP-14 is one of six-membrane-type (MT-) MMPs, a sub-family of the MMP superfamily, so named because they are membrane bound. MMP-15 is phylogenetically the closest MMP relative to MMP-14, however its inhibition has no effect on soluble endoglin production from placenta.Methods: Here we aimed to characterize the remaining four MT-MMPs (MMP-16, -17, -24 and -25) in severe early-onset pre-eclamptic placenta and assess their relative contribution to soluble endoglin production.Results: Immunolocalisation studies revealed MMP-16, -24 and -25 were localized to the syncytiotrophoblast, the same site as endoglin, whilst MMP-17 was predominantly localized to fetal vessels and underlying stroma. MMP-17 protein was significantly (p < 0.05) up-regulated in pre-eclamptic placentas compared to gestationally matched pre-term controls, whilst MMP-25 mRNA was significantly (p < 0.05) down regulated. siRNA knockdown of MMP-16, -17, -24 and -25 in syncytialised BeWo cells did not alter soluble endoglin production in vitro.Conclusion: This is the first study to characterize MT-MMP protein localization in human placenta and indicates that MMP-14 is the only MT-MMP that contributes to soluble endoglin production in pre-eclampsia. (C) 2012 Elsevier Ltd. All rights reserved.