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

Lead Research Organisation: University of Manchester
Department Name: Medical and Human Sciences

Abstract

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.

Technical Summary

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.

Publications

10 25 50
 
Description CMFT Project Grant
Amount £14,863 (GBP)
Organisation Manchester University NHS Foundation Trust 
Sector Public
Country United Kingdom
Start 01/2008 
End 01/2009
 
Description Don Jacobsen 
Organisation Cleveland Clinic
Department Department of Cellular & Molecular Medicine
Country United States 
Sector Academic/University 
PI Contribution Investigation of the mechanisms of homocysteine transport by placenta
Collaborator Contribution Synthesis and provision of radiolabelled homocysteine thiolactone, which following conversion to homosysteine, was used as radiotacer for transport assays.
Impact 19564394 20567909
Start Year 2009
 
Description Stuart Moat 
Organisation Cardiff University
Department Department of Medical Biochemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Investigations into homocysteine-folate-cobalamin interrelationships in pregnancy
Collaborator Contribution Measurement of homocysteine, folate and cobalamin in maternal and fetal plasma
Impact Article "Homocysteine-folate-cobalamin interrelationships and infant size at birth" (submission pending)
Start Year 2007
 
Description Developmental Physiology Conference 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact This is an annual conference aimed at bringing together people of mixed backgrounds (health practitioners, affected families, academic peers) with an interest in trying to understand the causes of Sudden Infant Death Syndrome (SIDS), and is sponsored by a family who sadly lost a daughter to SIDS. My talk entitled "Feeding the Baby: what's on the menu?" put forward the concept that early embryonic nutrition and placental function may have a role in susceptibility to SIDS, using folate as an example of a key nutrient that affects developmental outcome and utilising data obtained through this MRC Award.

After the talk, very positive comments were received across all members of the audience, and I have been invited back again as a Guest Speaker to present at their meeting in 2015 and elaborate further on this topic.
Year(s) Of Engagement Activity 2014