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Hum. Reprod. Advance Access originally published online on August 18, 2006
Human Reproduction 2006 21(10):2530-2537; doi:10.1093/humrep/del111
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Dimethylarginine dimethylaminohydrolase (DDAH) regulates trophoblast invasion and motility through effects on nitric oxide

L.J. Ayling1, G.St.J. Whitley1, J.D. Aplin2 and J.E. Cartwright1,3

1 Division of Basic Medical Sciences, St George’s, University of London, Cranmer Terrace, London and 2 Division of Human Development, Medical School, University of Manchester, St. Mary’s Hospital, Manchester, UK

3 To whom correspondence should be addressed at: Division of Basic Medical Sciences, St. George’s, University of London, Cranmer Terrace, London, SW17 ORE, UK. E-mail: j.cartwright{at}sgul.ac.uk

BACKGROUND: Invasion of trophoblast into the uterine environment is crucial for establishing a successful pregnancy. Physiological production of nitric oxide (NO) by extravillous trophoblasts results in significant pro-invasive effects. NO synthesis is competitively inhibited by methylated arginine analogues such as asymmetric dimethylarginine (ADMA) but not the enantiomer symmetric dimethylarginine (SDMA). Within cells, the concentration of ADMA is regulated by the activity of the enzyme dimethylarginine dimethylaminohydrolase (DDAH). The aim of this study was to examine DDAH expression and function in trophoblasts. METHODS AND RESULTS: DDAH-1 and DDAH-2 messenger RNA and protein were demonstrated in first trimester placental tissue, primary extravillous trophoblasts and extravillous trophoblast-derived cell lines. DDAH activity was demonstrated in both cells and tissue. Overexpression of DDAH-1 in trophoblasts led to a number of significant changes, including an 8-fold increase in enzymatic activity, a 59% decrease in production of ADMA (but not SDMA), a 1.9-fold increase in NO and a 1.6-fold increase in cyclic guanosine monophosphate (cGMP) production. Functional assays showed that increased DDAH activity led to significantly increased cell motility and invasion in response to hepatocyte growth factor (HGF). CONCLUSIONS: DDAH may play an important role in the regulation of extravillous trophoblast function via its effects on ADMA and NO production.

Key words: ADMA/asymmetric dimethylarginine/placenta/pregnancy


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