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.ectoplacental cone | fetus P reeclampsia (PE) is one of the most common pregnancy complications worldwide, affecting ∼3% to 8% of all pregnancies, and is a leading cause of perinatal and maternal morbidity and mortality (1). PE is characterized by placental hypoperfusion and shallow trophoblast invasion of uterine blood vessels (2) that is particularly evident in the severe cases that commence early in pregnancy (3). Adequate trophoblast invasion is vital to provide the embryo with access to oxygen and nutrients, and, in human and mouse, the placenta is thereby in direct contact with maternal blood. The clinical diagnostic criteria of this syndrome include widespread maternal endothelial dysfunction as evidenced by hypertension, proteinuria, and peripheral and/or cerebral edema (4). In addition to the maternal signs, PE is also frequently associated with intrauterine growth restriction (IUGR) and prematurity (5). The etiology of PE is unclear and the only known cure is delivery of the placenta. The upstream regulatory mechanisms remain elusive, as do the downstream consequences that lead to the maternal signs. Nevertheless, there is substantial evidence for contributing factors including abnormal placentation, particularly the invasive component. Restricted invasion is thought to be a reflection of defects in the cytotrophoblast (CTB) differentiation pathway that is required for uterine interstitial and endovascular invasion. Specifically, CTBs, which are epithelial cells of ectodermal origin, acquire vascularlike properties, and this transformation is dysregulated in PE (3, 6). The rudimentary endovascular invasion is thought to lead to the release of pathologic factors such as va...

Maternal obesity drives functional alterations in uterine NK cells

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HIF-KDM3A-MMP12 regulatory circuit ensures trophoblast plasticity and placental adaptations to hypoxia

“…Structural changes associated with tissue plasticity are engineered via activation of matrix metalloproteinases (MMPs) (27,28). MMPs are responsive to environmental signals and promote the movement of cells through tissue matrices, facilitate structural changes in blood vessel integrity, and contribute to morphogenesis of the placenta (18,27,(29)(30)(31).…”

Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia

“…A substantial body of data indicates that PE in humans is a consequence of placental abnormalities caused by inadequate invasion of the maternal uterine endometrium by embryonic cytotrophoblasts (12,13). In mice, giant trophoblast cells (GTCs), differentiated from trophoblast stem cells, mediate the early stages of this invasion, by producing matrix metalloproteinases (14,15).…”