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Therapeutic interventions to reverse fetoplacental vascular dysregulation and anatomical changes in fetal growth restriction


Project Description

Fetal growth restriction (FGR) is a serious pregnancy complication, which affects 3-8% of pregnancies and is associated with a significant increase in perinatal morbidity, mortality and stillbirth Associations between low birth weight and increased risk of cardiovascular disease in adulthood have also been well documented, with growing evidence that programming during prenatal life can predispose to cardiovascular disease in later life. In recent work we discovered that the fetoplacental circulation is the primary locus that defines vascular resistance in the umbilico-placental circulation. In idiopathic FGR we found that the fetoplacental vasculature is dysfunctional in this disease, resulting in reduced flow mediated vasodilation (FMVD) and presenting as a general increased placental vascular resistance.

Further evidence suggests that the fetoplacental microcirculation becomes inflamed in FGR. Little attention has been given to potential anatomical alterations to the vessel walls of the fetoplacental circulation in FGR. Anatomical change through vascular wall thickening, normally attributed to vascular stiffening in aging vessels is one possible feature that might explain prolonged poor umbilico-placental perfusion that is a feature of some idiopathic cases of FGR.

This study aims to stratify high placental resistance FGR cases according to (i) fetal plasma endocrine imbalance, (ii) inherent vascular dysregulation in response to shear stress and (iii) anatomical vascular aetiology. A translational arm will focus on safe pregnancy therapies designed to promote the eNOS signalling pathway within the fetoplacental circulation to counteract the high resistance often found in this disease.

The project aims to test whether potentiation of the eNOS signalling pathway, through a variety of therapeutic strategies, will provide vascular protection to the fetoplacental circulation in FGR pregnancy, by reducing resistance to blood flow and counteracting inflammation that precedes vascular wall thickening.

Using fresh placentas from FGR pregnancies, collected at the point of delivery from women who had been recruited at the Manchester Placenta Clinic, the project will utilise whole tissue and cellular models to evaluate and type case-specific physiological and biochemical vascular responses alongside extracellular matrix ultra-structural changes in the stem artery vessel wall. These models will include the in vitro dual perfusion model of human placental, isolated arterial endothelial cells (HPAECs) grown under laminar flow culture at defined shear stresses and isolated placental myocytes, as well as structural analysis of fixed placental vessels.

The Maternal and Fetal Health Research Centre is the largest translational placental research group in Europe, with interests in placental development, function and obstetric pathology, including stillbirth, fetal growth restriction, preeclampsia, obesity and diabetes; a drive towards diagnostic and translational medicine. Drs Brownbill and Greenwood have more than 20 years of experience in placental physiology (including placental transfer and vascular tone); Dr Johnstone is a clinician scientist with a research focus on the stratification of FGR and wide experience of placental imaging. The supervisory team are all experienced in post graduate student supervision.

Laboratory skills and techniques for training: microscopy, isolation and culture of human placental chorionic plate endothelial cells (HPAECs) and placental myocytes, shear stress cell-flow culture, ex vivo dual perfusion of the human placental lobule, protein biochemistry, cell signalling and biochemical assays, immunohistochemistry. The student will be expected to participate in the PhD training programme.

Candidates are expected to hold a minimum upper-second (or equivalent) undergraduate degree in a related biomedical/biological science, reproductive health or analytical chemistry. A Masters qualification in a similar area would be an advantage as would previous experience of vascular physiology.

This 3-year full-time PhD is open to candidates able to provide evidence of self-arranged funding/sponsorship.

Any enquiries relating to the project and/or suitability should be directed to Dr Brownbill. Applications are invited on an on-going basis but early expression of interest is encouraged.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.

References

Jones, S., Bischof, H., Johnstone, E., Greenwood, S, Wareing, M., Sibley, C., Brownbill, P. (2013) Endothelial dysfunction of the fetoplacental circulation contributes to the increased vascular resistance observed in fetal growth restriction. Placenta 34, A22

Jones, S., Bischof, H., Johnstone, E., Greenwood, S, Wareing, M., Sibley, C., Brownbill, P. (2013) Fetal inflow hydrostatic pressure measurements in the ex-vivo perfused placenta correlate with umbilical artery Doppler RI and PI values. Placenta 34, A64

Jones, S., Bischof, H., Johnstone, E., Lang, I., Desoye, G., Greenwood, S., Wareing, M., Sibley, C., Brownbill. P. Elevated shear stress in fetal growth restriction results in a sustained increase in endothelial expression and activation of eNOS and iNOS in the fetoplacental vasculature. Placenta 34, A64

Lattey, K., Bischof, H., Hayward, C., Brownbill, P., Jones, S. (2014) TRPV4; a potential new target to increase placental blood flow in fetal growth restricted pregnancies? Heart 100, A96

Junaid TO, Brownbill P, Chalmers N, Johnstone ED, Aplin JD. (2014) Fetoplacental vascular alterations associated with fetal growth restriction. Placenta 35(10):808-15

How good is research at University of Manchester in Clinical Medicine?

FTE Category A staff submitted: 136.18

Research output data provided by the Research Excellence Framework (REF)

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