title: Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction.
abstract: 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.
authors.affiliation: Department of Anatomy, University of California, San Francisco, CA 94143, USA.
authors.forename: Vicki
authors.initials: V
authors.lastname: Plaks
authors.forename: Julie
authors.initials: J
authors.lastname: Rinkenberger
authors.forename: Joanne
authors.initials: J
authors.lastname: Dai
authors.forename: Margaret
authors.initials: M
authors.lastname: Flannery
authors.forename: Malin
authors.initials: M
authors.lastname: Sund
authors.forename: Keizo
authors.initials: K
authors.lastname: Kanasaki
authors.forename: Wei
authors.initials: W
authors.lastname: Ni
authors.forename: Raghu
authors.initials: R
authors.lastname: Kalluri
authors.forename: Zena
authors.initials: Z
authors.lastname: Werb
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004624:Embryo Transfer; D005260:Female; D005317:Fetal Growth Retardation / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D005333:Fetus / Q000002:abnormalities / Q000201:enzymology; D006801:Humans; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010920:Placenta / Q000002:abnormalities / Q000201:enzymology; D010929:Placentation / Q000235:genetics; D011225:Pre-Eclampsia / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D011247:Pregnancy
chemical_list: C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: ectoplacental cone; fetus