ADENOSINE

The role of adenosine in placental development and function

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 Obiettivo del progetto (Objective)

'Altered fetal growth patterns, i.e. reduced growth in utero (intrauterine growth restriction, IUGR) are associated with perinatal morbidity as well as adverse consequences in adult life, e.g. cardiovascular disease. A prevailing hypothesis regarding the pathogenesis of reduced growth in utero is the “ischemic model” where abnormal placental bed vascular pathology with reduced nutrient and oxygen delivery to the intervillus space as a result of diminished placental perfusion contributes to suboptimal fetal growth in the second half of pregnancy. Amino acids are an important nutrient during fetal development and their concentration and placental transport are significantly lower in growth-restricted infants. Recent studies indicate that a variety of signals such as adenosine are produced in response to hypoxia in tissues and are higher in women with preeclampsia and growth-restricted infants. However, to date there is little information about the role of adenosine in pregnancy and the placenta. Therefore, the focus of this proposal is to investigate the effect and mechanism of the hypoxia-inducible signal adenosine on placental development and placental amino acid transport.'

Introduzione (Teaser)

Scientists investigated the expression of a hypoxia-associated molecule with elevated levels in a severe form of hypertension in pregnancy. Tests in cell and tissue cultures pointed to potential cellular mechanisms of reduced embryo growth.

Descrizione progetto (Article)

During the late second and third trimester of pregnancy babies typically grow by leaps and bounds. Sometimes complications can reduce that growth and lead to morbidity in the few weeks before and after birth, and even later in life. One potential cause could be an inadequate supply of oxygen (hypoxia or ischaemia) and nutrients to the developing embryo from abnormal vascular morphology or placental function.

Preeclampsia (PE) is a pathological condition during pregnancy characterised by an abrupt increase in blood pressure (hypertension). There is no effective treatment or cure and it is a leading cause of maternal and infant morbidity and mortality worldwide. Women with PE also have higher levels of adenosine, associated with hypoxia of tissues, as do growth-restricted infants. Furthermore, women with PE have elevated levels of proteins in the urine. Proteins are formed from amino acids and their concentration as well as placental transport is reduced in growth-restricted infants.

Taken together, the data suggest a link between diminished amino acid transport and a hypoxia-induced adenosine signal, and a role for both in growth-restricted infants. This link was investigated by scientists with EU funding of the project 'The role of adenosine in placental development and function' (ADENOSINE). Researchers investigated the hypothesis using cultures of human trophoblast cells (that play an important role in placental development) and of placental tissues.

Stimulation of the adenosine receptor A2B reduced trophoblast migration, possibly due partially to reduced activity of an enzyme associated with angiogenesis (blood vessel formation). Furthermore, hypoxia increased A2A and A2B adenosine receptor expression on trophoblast cells. Although there was no inhibition or activation effect of adenosine receptors on placental amino acid transporter activity, reduced activity was seen with decreasing oxygen concentrations.

ADENOSINE studies suggest a role of the A2B adenosine receptor in placental development. Modulation of its expression by hypoxia also diminished amino acid transport. The potential role of adenosine in PE opens the door to future research to identify other targets for therapeutic intervention in women at high-risk for PE.