Direct Effects of Cortisol on Placental Nutrient Transfer Capacity.
Lead Research Organisation:
St Mary's Hospital, Manchester
Department Name: Obstetrics and Gynaecology
Abstract
During pregnancy, the developing baby receives nutrients from mother via the placenta. However, in the common pregnancy complication, intrauterine growth restriction (IUGR), blood flow to the placenta and nutrient transfer are dramatically reduced. Affected babies are also at increased short term risks during labour and are at increased risk of heart disease, diabetes and raised blood pressure in adult life.
Cortisol is a steroid hormone whose levels are increased by stress. Recent research has shown that high cortisol levels can alter baby‘s growth and development. If the mother is stressed during pregnancy, for example following a bereavement, her blood cortisol levels rise. Preterm labour treatments also increase cortisol in Mum‘s blood. The placenta has an inactivating enzyme to protect the baby from increased cortisol levels in Mother‘s blood. In IUGR, however, levels of this enzyme are thought to be reduced.
It is not known how cortisol alters the way the placenta works. My study will investigate if cortisol alters blood flow by assessing blood vessel behaviour directly. I will also look at how cortisol alters the proteins in the placenta that move nutrients to the baby during pregnancy.
Understanding how cortisol alters the function of the placenta will assist design of future treatment strategies for IUGR and ensure the safe use of steroid hormones in preterm labour.
Cortisol is a steroid hormone whose levels are increased by stress. Recent research has shown that high cortisol levels can alter baby‘s growth and development. If the mother is stressed during pregnancy, for example following a bereavement, her blood cortisol levels rise. Preterm labour treatments also increase cortisol in Mum‘s blood. The placenta has an inactivating enzyme to protect the baby from increased cortisol levels in Mother‘s blood. In IUGR, however, levels of this enzyme are thought to be reduced.
It is not known how cortisol alters the way the placenta works. My study will investigate if cortisol alters blood flow by assessing blood vessel behaviour directly. I will also look at how cortisol alters the proteins in the placenta that move nutrients to the baby during pregnancy.
Understanding how cortisol alters the function of the placenta will assist design of future treatment strategies for IUGR and ensure the safe use of steroid hormones in preterm labour.
Technical Summary
Aims. Cortisol directly affects placental function, resulting in reduced nutrient transfer to the developing fetus, via: (1) alteration in blood flow in fetoplacental vessels; (2) reduction in the expression and/or activity of amino acid transport systems. I hypothesize that these effects of cortisol significant cause of IUGR. I will determine: (1) effects of glucocorticoids on placental vascular contractility, (2) effects of glucocorticoids on syncytiotrophoblast amino acid transporter expression and activity and (3) whether these effects are altered in IUGR.
Objectives & Design. This will be a laboratory based project. It has been divided into three sections to determine the effect of cortisol on 1) blood vessel contractility, 2) syncytiotrophoblast amino acid transporter expression and 3) whether these effects are altered in IUGR, and if they are related to altered 11-?-HSD-2 expression and/or GR and MR.
Methodology. Placental blood vessels will be studied using isometric wire myography. The effect of cortisol on the activity and expression System A will be measured in fresh placental explants. System A activity will be measured as Na+-dependent MeAIB uptake, and I will use quantitative polymerase chain reaction (Q-PCR) and Western blotting to measure expression of the three transporter isoforms (SNAT1, 2 and 4). To determine whether excessive glucocorticoid exposure plays a role in the pathogenesis of IUGR, I will examine the effects of cortisol on vascular contractility and system A activity in IUGR placentae. 11-?-HSD-2 mRNA expression is reduced in IUGR placentas. I will determine whether i) protein production of 11-?-HSD-2 is downregulated and ii) glucocorticoid receptors, GR and MR, are aberrantly expressed in IUGR placentas using QPCR. Protein production and localisation will be determined using Western blotting and IHC.
Scientific and Medical Opportunities of the Study
Understanding the consequences of exogenous glucocorticoid treatment during pregnancy is of fundamental importance. Glucocorticoids are given to women who are at risk of preterm labour, to decrease the risk of respiratory disease and brain haemorrhages in the neonate. Inevitably, glucocorticoids are given to women who will go to term and this research will tell us what effect steroids have on the placental function. This will be of immediate benefit to enable informed choices to be made in individual cases, to balance risk and benefits of maternal corticosteroid administration. In the longer term, increased understanding of the pathogenesis of IUGR, and the mechanism of subsequent cardiovascular disease in later life is of paramount importance.
Objectives & Design. This will be a laboratory based project. It has been divided into three sections to determine the effect of cortisol on 1) blood vessel contractility, 2) syncytiotrophoblast amino acid transporter expression and 3) whether these effects are altered in IUGR, and if they are related to altered 11-?-HSD-2 expression and/or GR and MR.
Methodology. Placental blood vessels will be studied using isometric wire myography. The effect of cortisol on the activity and expression System A will be measured in fresh placental explants. System A activity will be measured as Na+-dependent MeAIB uptake, and I will use quantitative polymerase chain reaction (Q-PCR) and Western blotting to measure expression of the three transporter isoforms (SNAT1, 2 and 4). To determine whether excessive glucocorticoid exposure plays a role in the pathogenesis of IUGR, I will examine the effects of cortisol on vascular contractility and system A activity in IUGR placentae. 11-?-HSD-2 mRNA expression is reduced in IUGR placentas. I will determine whether i) protein production of 11-?-HSD-2 is downregulated and ii) glucocorticoid receptors, GR and MR, are aberrantly expressed in IUGR placentas using QPCR. Protein production and localisation will be determined using Western blotting and IHC.
Scientific and Medical Opportunities of the Study
Understanding the consequences of exogenous glucocorticoid treatment during pregnancy is of fundamental importance. Glucocorticoids are given to women who are at risk of preterm labour, to decrease the risk of respiratory disease and brain haemorrhages in the neonate. Inevitably, glucocorticoids are given to women who will go to term and this research will tell us what effect steroids have on the placental function. This will be of immediate benefit to enable informed choices to be made in individual cases, to balance risk and benefits of maternal corticosteroid administration. In the longer term, increased understanding of the pathogenesis of IUGR, and the mechanism of subsequent cardiovascular disease in later life is of paramount importance.