Authors: Drewlo, Sascha; Czikk, Marie; Baczyk, Dora; Lye, Stephen; Kingdom, John

Source: Human Reproduction, Volume 26, Number 5, 9 May 2011 , pp. 1025-1034(10)

Publisher: Oxford University Press

Abstract:

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 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.

METHODS AND RESULTS

In floating first trimester villous explants we demonstrated increased mRNA (2.5-fold, n = 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 = 7, P< 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 = 8), compared with preterm (1.7 ± 0.17 pg/µg, n = 9) and term controls (1.6 ± 0.16 pg/µg, n = 9; P< 0.01; quantified by enzyme-linked immunosorbent assay and visualized using immunohistochemistry) with reduced GCM1 expression, mostly in the pathologic syncytial knots.

CONCLUSIONS

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.

Keywords: tissue inhibitors of metalloproteinase-4; pre-eclampsia; glial cell missing-1; placenta; trophoblast

Document Type: Research article

DOI: http://dx.doi.org/10.1093/humrep/der053

Publication date: 2011-05-09

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• Human Reproduction features full-length, peer-reviewed papers reporting original research, clinical case histories, as well as opinions and debates on topical issues. Papers published cover the scientific and medical aspects of reproductive physiology and pathology, endocrinology, andrology, gonad function, gametogenesis, fertilization, embryo development, implantation, pregnancy, genetics, genetic diagnosis, oncology, infectious disease, surgery, contraception, infertility treatment, psychology, ethics and social issues. The highest scientific and editorial standard is maintained throughout the journal along with a rapid rate of publication.

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