TY - JOUR
T1 - Matrix metalloproteinase-9 deficiency phenocopies features of preeclampsia and intrauterine growth restriction
AU - Plaks, Vicki
AU - Rinkenberger, Julie
AU - Dai, Joanne
AU - Flannery, Margaret
AU - Sund, Malin
AU - Kanasaki, Keizo
AU - Ni, Wei
AU - Kalluri, Raghu
AU - Werb, Zena
PY - 2013/7/2
Y1 - 2013/7/2
N2 - 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.
AB - 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.
KW - Ectoplacental cone
KW - Fetus
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U2 - 10.1073/pnas.1309561110
DO - 10.1073/pnas.1309561110
M3 - Article
C2 - 23776237
AN - SCOPUS:84879725674
SN - 0027-8424
VL - 110
SP - 11109
EP - 11114
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 27
ER -