Aberrant first trimester placental endothelial cell biology in fetal growth restriction

The size we are born should be determined by the genes we inherit from our parents, however many babies are born smaller than they should be. Some of these babies may suffer from a form of starvation during pregnancy, not receiving the vital oxygen and nutrients they need from their mother. It is thought that babies suffering the effects of starvation during pregnancy are not only more likely to have problems at birth but these stay with them throughout their life with long lasting and damaging consequences. Smaller babies are more likely to suffer from health problems in later life, including an increased risk of cardiovascular disease and diabetes. Estimates suggest that this affects up to 3 million individuals in the UK alone and, over their lifetime, this places a huge financial burden on health services. In order for a baby to receive the nourishment it needs from its mother during pregnancy it must have a healthy placenta with a rich network of blood vessels. This network develops early in pregnancy long before the time when an accurate measure of the baby's growth can be made. Failure of the placental blood vessels to develop into this network is a common feature of pregnancies with small babies. With the help of our clinical colleagues we have used a technique called uterine artery Doppler ultrasound to identify pregnancies that are likely to result in a small baby and have found that the placental blood vessels are different to those from pregnancies with a normal sized baby. The aim of this project is to look more closely at why these cells are different. We will look at the ability of the cells that form blood vessels to grow and form vascular networks. We will also see why cells from pregnancies that would result in small babies are more sensitive to factors that result in their death. It is only by understanding, why the cells from some pregnancies are different that we may one day be able to develop ways of managing these differences. Having babies that are born the right size will help them in early life but also help keep them healthy for longer as an adult.

Poor placental vascular development at term is seen in pregnancies complicated by fetal growth restriction (FGR). FGR affects 5-8% of human pregnancies worldwide and is a major cause of neonatal morbidity and mortality. Although the pathological changes responsible are believed to occur early in pregnancy, studies directed towards the cellular and molecular mechanisms have been hampered by the lack of appropriate cellular models and the ability to determine, at a clinically relevant time, which pregnancies are at risk of developing FGR. Studies have established a correlation between high first trimester uterine artery Doppler resistance indices (hRI) and birth weight due to placental insufficiency. We will use Doppler ultrasound in the first trimester as a proxy measure of placental function. Using this unique approach and methods developed here to isolate first trimester placental endothelial cells (PEC), we have found that PEC isolated from pregnancies with hRI are more sensitive to apoptotic factors than cells from pregnancies with a normal RI (nRI). It is our hypothesis that poor placental capillary network development is the result of changes to PEC migration/motility and/or sensitivity to apoptotic stimulation and we will seek to establish the mechanism of these differences at a cellular and molecular level. We will investigate whether these differences are the result of changes in gene and/or protein expression in PEC. As placental angiogenesis and PEC survival may also be dependent on factors secreted by surrounding placental stromal cells (PSC) we will determine whether they support an anti-angiogenic, pro-apoptotic phenotype in hRI pregnancies by characterizing differences in gene expression and protein secretion profiles. In vitro findings will be supported by immunohistochemical studies performed on first trimester placental tissue sections.

The major beneficiaries of this research will be as follows:

1) Students at St George's. We actively participate in the teaching of undergraduate medical, biomedical science degree students and post-graduate MRes, PhD and MDRes students. The best way to inspire this group is for them work alongside young enthusiastic scientists. We would anticipate the appointment of two such individuals to the group will provide such an environment. The results obtained and the techniques developed will have a longer term impact on the education of these and future students that may join the group.

2) Clinicians within the SouthWest London Academic Network will benefit from an increased awareness of the research in this area through the Grand Round seminar series and an annual St George's Research Day organised by members of our research institute. Other clinical beneficiaries will be members of the Department of Obstetrics and Gynaecology and, in particular, those within the Fetal Medicine Unit here at St George's. Findings will be disseminated more widely to similar beneficiaries outside St George's through targeted press releases from our media office and through attendance at Clinical meetings such as Society of Reproductive Investigation held internationally each year. In particular, International dissemination will be achieved through the TRUFFLE group of collaborators, of which St Georges is a member. The TRUFFLE group are responsible for the conduct of a multi-centre European study on the diagnosis and management of early-onset FGR (Lancet 2014; in press).

3) The aim of this proposal is to improve our understanding of the fundamental processes controlling placental angiogenesis in both health and disease. We do not anticipate any immediate impact on the commercial sector however increased knowledge in this important area may identify therapeutic targets or provide diagnostic tools that could ultimately change clinical practice.

4) There are patient liaison groups within the hospital that may be interested as might Action on Pre-eclampsia (APEC) a group that aims to raise public and professional awareness of pre-eclampsia, a syndrome often associated with FGR. Charities that directly fund research in to child health such as Action Medical Research, Wellbeing of Women, Tommy's Campaign may also benefit from the increased knowledge obtained as might the the British Heart Foundation because of the direct link with increased cardiovascular disease in later life.