Department of Anatomy, University of California, San Francisco, CA 94143, USA.
Proc Natl Acad Sci U S A. 2013 Jul 2;110(27):11109-14. doi: 10.1073/pnas.1309561110. Epub 2013 Jun 17.
The pregnancy complication preeclampsia (PE), which occurs in approximately 3% to 8% of human pregnancies, is characterized by placental pathologies that can lead to significant fetal and maternal morbidity and mortality. Currently, the only known cure is delivery of the placenta. As the etiology of PE remains unknown, it is vital to find models to study this common syndrome. Here we show that matrix metalloproteinase-9 (MMP9) deficiency causes physiological and placental abnormalities in mice, which mimic features of PE. As with the severe cases of this syndrome, which commence early in gestation, MMP9-null mouse embryos exhibit deficiencies in trophoblast differentiation and invasion shortly after implantation, along with intrauterine growth restriction or embryonic death. Reciprocal embryo transfer experiments demonstrated that embryonic MMP9 is a major contributor to normal implantation, but maternal MMP9 also plays a role in embryonic trophoblast development. Pregnant MMP9-null mice bearing null embryos exhibited clinical features of PE as VEGF dysregulation and proteinuria accompanied by preexisting elevated blood pressure and kidney pathology. Thus, our data show that fetal and maternal MMP9 play a role in the development of PE and establish the MMP9-null mice as a much-needed model to study the clinical course of this syndrome.
妊娠并发症子痫前期（PE）在大约 3%至 8%的人类妊娠中发生，其特征是胎盘病理，可导致胎儿和产妇发病率和死亡率显著增加。目前，唯一已知的治疗方法是分娩胎盘。由于子痫前期的病因仍不清楚，因此找到研究这种常见综合征的模型至关重要。在这里，我们表明基质金属蛋白酶-9（MMP9）缺乏会导致小鼠出现生理和胎盘异常，这些异常类似于 PE 的特征。与该综合征的严重病例一样，MMP9 缺陷型小鼠胚胎在着床后不久就表现出滋养细胞分化和侵袭的缺陷，同时伴有宫内生长受限或胚胎死亡。胚胎相互转移实验表明，胚胎 MMP9 是正常着床的主要贡献者，但母体 MMP9 也在胚胎滋养细胞发育中发挥作用。携带 MMP9 缺陷型胚胎的妊娠 MMP9 缺陷型小鼠表现出 PE 的临床特征，如 VEGF 失调和蛋白尿，同时伴有先前存在的高血压和肾脏病理。因此，我们的数据表明胎儿和母体 MMP9 在 PE 的发展中发挥作用，并确立了 MMP9 缺陷型小鼠作为研究该综合征临床过程的急需模型。
