Mechanisms of homocysteine transport by human placenta:Relationship to placental vascular distensibility and birthweight

Low birthweight (LBW) infants are at greater risk of developmental delay and cerebral palsy in later childhood than those of normal birthweight. In adult life, LBW may predispose to cardiovascular disease. This may be linked to a higher concentration of an amino acid called homocysteine which damages blood vessel walls.

In pregnancy, sub-optimal folate or vitamin B12 status may contribute to raised homocysteine concentrations in maternal plasma and reduced fetal growth. How homocysteine is transported by the placenta is unknown. It is possible that homocysteine-induced damage to placental blood vessels provides a causative link between impaired placental function and LBW.

Our project will identify transport systems that carry homocysteine across the placenta in normal pregnancies and investigate whether these transporters are modulated by the vitamins folate and B12, micronutrients important in the metabolic conversion of homocysteine. We plan to explore relationships between homocysteine concentrations in cord blood, normal variations in infant size at birth, and the distensible properties of placental arterial vessels as a model of fetal vessels in which vascular function can be examined.

We hope that our work will lead to new initiatives together with a continuum of care to improve fetal growth and health of newborn infants.

Elevated plasma homocysteine, a risk factor for vascular disease, is associated with poor pregnancy and neonatal outcome of varying severity including a reduced birthweight. Maternal and fetal plasma homocysteine concentrations are positively correlated from early in pregnancy. Net flux of homocysteine across the placenta is indicated by the statistically significant difference in umbilical vein-artery homocysteine concentration. The involvement of carrier-mediated mechanisms in homocysteine transport across the placenta has not been examined. This project will test the hypothesis that uptake and efflux mechanisms for L-homocysteine exist in placental syncytiotrophoblast. Our preliminary observations suggest the involvement of amino acid transporter system y+L in homocysteine uptake and we hypothesise that homocysteine efflux is mediated by system L amino acid transporter. We propose that these transport mechanisms for homocysteine are functional from early pregnancy onwards, and that homocysteine as a transport substrate, could alter fetal delivery of essential amino acids also transported by these mechanisms, thereby influencing fetal growth and development. We further suggest that the activity of these transporters is modulated by folate and vitamin B12, vitamins involved in the metabolic cycling of homocysteine. We also postulate that the damaging vascular properties of homocysteine could induce deleterious effects on the fetal and/or placental vasculature, increasing vascular resistance, which would impact on fetal development. We wish to examine these hypotheses by characterising the transport mechanisms for homocysteine in human placenta and their modulation by folic acid and vitamin B12, determining whether transporter activity is correlated with fetal venous homocysteine concentration and anthropometric measurements of size at birth, and by examining the relationship between fetal arterial homocysteine concentration and fetal arterial vessel function, determined in chorionic plate arteries as a model of fetal arterial vessels with size characteristics of resistance vessels. This proposal will further our understanding of transporter pathologies in human placenta thereby contributing to the scientific framework for advancing the management of complications in pregnancy.