BACKGROUND<\/p>\n
Severe pre-eclampsia (sPE) causes significant maternal morbidity and intrauterine growth restriction as a result of severe placental dysfunction. Defects in the formation of both extra-villous and villous trophoblast are characteristic of this disease. The outer syncytiotrophoblast layer covering the placental villi develops syncytial knots and focal necrosis while reduced invasion of the extra-villous trophoblast results in a reduced maternal blood supply and ischemia of the placental villi. The transcription factor glial cell missing-1 (GCM1) regulates formation of both types of trophoblast. GCM1 expression is reduced in placental villi of women with sPE but the functional downstream consequences of reduced GCM1 expression are unknown.<\/p>\n
METHODS AND RESULTS<\/p>\n
In floating first trimester villous explants we demonstrated increased mRNA (2.5-fold, n<\/I> = 12) and protein level (9.8-fold) of tissue inhibitor of metalloproteinase-4 (TIMP4) following repression of GCM1 (70 ± 7%) by small interfering-RNA, using RT–PCR and western blot, respectively. Similar increases in TIMP4 mRNA (4.2-fold, n<\/I> = 7, P<\/I>< 0.001 versus control) and protein levels were found following gene silencing of GCM1 in BeWo cells (<90% knock down of protein). TIMP4 protein was increased in placenta from women with sPE (3.5 ± 0.4 pg\/µg, n<\/I> = 8), compared with preterm (1.7 ± 0.17 pg\/µg, n<\/I> = 9) and term controls (1.6 ± 0.16 pg\/µg, n<\/I> = 9; P<\/I>< 0.01; quantified by enzyme-linked immunosorbent assay and visualized using immunohistochemistry) with reduced GCM1 expression, mostly in the pathologic syncytial knots.<\/p>\n
CONCLUSIONS<\/p>\n
TIMP4 is a downstream target of GCM1 that may link the consequences of reduced GCM-1-directed trophoblast differentiation to histologic and functional components of disordered placentation in sPE.<\/p>\n","protected":false},"excerpt":{"rendered":"
BACKGROUND Severe pre-eclampsia (sPE) causes significant maternal morbidity and intrauterine growth restriction as a result of severe placental dysfunction. Defects in the formation of both extra-villous and villous trophoblast are characteristic of this disease. The outer syncytiotrophoblast layer covering the … Continue reading