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

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.

Effect of first-trimester serum from pregnant women with high-resistance uterine artery Doppler resistance on extravillous trophoblast invasion.

BACKGROUND: Abnormal uterine artery Doppler indices are associated with pregnancy complications such as pre-eclampsia and intrauterine growth restriction. Poor trophoblast invasion may be a consequence of, or be associated with, abnormal Doppler indices. OBJECTIVE: To evaluate in vitro trophoblast function following exposure to first-trimester serum from pregnancies with high uterine artery Doppler resistance indices. METHODS: Doppler ultrasound examination of the maternal uterine arteries was performed on women at 10-14 weeks' gestation. Serum was collected from women with bilateral uterine artery notches with resistance indices above the 95th centile and from patients with normal uterine artery indices. The effect of serum on trophoblast invasion was determined using an established in vitro model from the extravillous trophoblast-derived cell line SGHPL-4. RESULTS: Trophoblastic invasion was significantly reduced when treated with serum from women with high-resistance compared with normal-resistance uterine artery Doppler indices (P < 0.05). CONCLUSION: Maternal serum in the first trimester of pregnancy from patients with high-resistance uterine artery Doppler indices appears to inhibit trophoblast invasion. This experimental model allows further investigation of factors responsible and the evaluation of therapeutic strategies.

The evolution of sex chromosomes.

Mammalian sex chromosomes appear, behave and function differently than the autosomes, passing on their genes in a unique sex-linked manner. The publishing of Ohno's hypothesis provided a framework for discussion of sex chromosome evolution, allowing it to be developed and challenged numerous times. In this report we discuss the pressures that drove the evolution of sex and the mechanisms by which it occurred. We concentrate on how the sex chromosomes evolved in mammals, discussing the various hypotheses proposed and the evidence supporting them.

Early origins of the X and Y chromosomes: lessons from tilapia.

Differentiated sex chromosome pairs in diverse species display certain common characteristics, normally comprising one largely heterochromatic genetically inactive chromosome and one euchromatic genetically active chromosome (e.g. the mammalian Y and X respectively). It is widely accepted that dimorphic sex chromosomes evolved from homologous pairs of autosomes. Although the exact mechanisms through which the pair diverged are not fully understood, an initial suppression of recombination in the sex-determining region is required by all of the major theories. Here we address the question of the mechanism by which this initial suppression of recombination occurs. Our model postulates that the stochastic, de novo accumulation of heterochromatin in the sex determining region can delay pairing of the sex chromosomes in meiosis, resulting in a decrease in recombination. Data to support this model is presented from the cichlid fish, Oreochromis niloticus. Although such a decrease would in most circumstances be evolutionarily disadvantageous, if the region concerned included the major sex determining gene and other gene(s) with sex-specific functions, then this would be selectively advantageous and could trigger the process(es) which, ultimately, lead to the differentiation of the sex chromosomes.