Translational Obstetrics Group, Mercy Hospital for Women, University of Melbourne, Heidelberg, Australia; Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, Heidelberg, Australia.
Centre for Cancer Research, Monash Institute of Medical Research, Monash University, Clayton, Australia.
Am J Pathol. 2012 Mar;180(3):888-894. doi: 10.1016/j.ajpath.2011.11.014. Epub 2012 Jan 31.
Soluble endoglin is an anti-angiogenic protein that is released from the placenta and contributes to both maternal endothelial dysfunction and the clinical features of severe preeclampsia. The mechanism through which soluble endoglin is released from the placenta is currently unknown; however, recent work in colorectal cancer identified matrix metalloproteinase 14 (MMP-14) as the cleavage protease of endoglin. To determine whether this is also the mechanism responsible for soluble endoglin release in preeclampsia, we investigated the expression of MMP-14 within the placenta and the effects of its inhibition on soluble endoglin release. Placentas were obtained from severe, early onset preeclamptic pregnancies (n = 8) and gestationally matched preterm controls (n = 8). MMP-14 was predominately localized to the syncytiotrophoblast. Results from a proximity ligation assay showed protein interactions between endogenous MMP-14 and endoglin within the preeclamptic placenta. To demonstrate that this interaction produces soluble endoglin, we treated trophoblastic BeWo cells with either a broad-spectrum MMP inhibitor (GM6001) or MMP-14 siRNA. Both treatments produced a decrease in soluble endoglin (P ≤ 0.05). Treatment of mice bearing BeWo xenografts with GM6001 decreased circulating soluble endoglin levels in mouse serum (P ≤ 0.05). These findings indicate that MMP-14 is the likely cleavage protease of endoglin in the setting of preeclampsia. This approach provides a novel method for the development of potential therapeutics to reduce circulating soluble endoglin and ameliorate the clinical features of severe preeclampsia.
可溶性内皮糖蛋白是一种抗血管生成蛋白，它从胎盘释放出来，导致母体血管内皮功能障碍和严重先兆子痫的临床特征。可溶性内皮糖蛋白从胎盘释放的机制目前尚不清楚；然而，最近在结直肠癌中的研究发现基质金属蛋白酶 14（MMP-14）是内皮糖蛋白的切割蛋白酶。为了确定这是否也是先兆子痫中可溶性内皮糖蛋白释放的机制，我们研究了 MMP-14 在胎盘内的表达及其对可溶性内皮糖蛋白释放的抑制作用。从严重的早发型先兆子痫妊娠（n = 8）和妊娠时间匹配的早产对照组（n = 8）中获得胎盘。MMP-14 主要定位于合体滋养层。邻近连接测定的结果显示，在先兆子痫的胎盘内，内源性 MMP-14 和内皮糖蛋白之间存在蛋白相互作用。为了证明这种相互作用产生可溶性内皮糖蛋白，我们用广谱 MMP 抑制剂（GM6001）或 MMP-14 siRNA 处理滋养层 BeWo 细胞。两种处理均导致可溶性内皮糖蛋白减少（P ≤ 0.05）。用 GM6001 处理携带 BeWo 异种移植物的小鼠，可降低小鼠血清中循环可溶性内皮糖蛋白水平（P ≤ 0.05）。这些发现表明，在先兆子痫中，MMP-14 可能是内皮糖蛋白的切割蛋白酶。这种方法为开发潜在的治疗方法提供了一种新的途径，以减少循环可溶性内皮糖蛋白并改善严重先兆子痫的临床特征。
