Dr Lynda Harris PhD

• International Federation of Placenta Associations
• The Physiological Society
• The Biochemical Society
• The British Society for Cell Biology
• The British Society for Developmental Biology
• The American Society for Matrix Biology
• The British Society for Matrix Biology

Trophoblast invasion and vascular remodelling in pregnancy

During the first twenty weeks of pregnancy, extravillous trophoblasts (EVT), an invasive subset of cells derived from the placenta, invade the wall of the uterus and remodel the uterine spiral arteries. This process causes the arteries to become heavily dilated and ensures that blood is delivered to developing placenta at an optimal rate for nutrient exchange. Successful vascular transformation is crucial to maintain a healthy pregnancy; impaired remodelling is associated with an increased risk of second trimester miscarriage, pre-term birth, pre-eclampsia and fetal growth restriction.

My research investigates the mechanisms employed by EVT to colonize and remodel the uterine spiral arteries. I have shown that:

• EVT can induce apoptosis of endothelial cells and smooth muscle cells (SMC) in the spiral artery wall, via production of Fas ligand and TNF-alpha-related apoptosis-inducing ligand (TRAIL)
• EVT produce enzymes called matrix metalloproteinases (MMP) that degrade the vascular extracellular matrix
• MMP activity at the leading edge of migrating EVT, and subsequent EVT invasion, is regulated in part by inducible nitric oxide synthase (iNOS)
• Soluble factors present in the blood of women diagnosed with the serious pregnancy complication of pre-eclampsia inhibit EVT invasion in vitro

Currently we are investigating how elastin in the walls of the spiral arteries is broken down, as effective vasodilatation cannot be achieved unless elastic fibres are eliminated. We are:

• investigating the role of MMP-12, a potent elastolytic enzyme that is highly expressed in EVT, in mediating elastin breakdown
• assessing whether the small, bioactive peptides that are released when elastin is degraded can promote EVT invasion and enhance arterial remodelling
• determining whether MMP-12 expression or activity is reduced in women with pre-eclampsia

During the very early stages of remodelling, uterine natural killer (uNK) cells are observed in close association with the spiral arteries, prior to the arrival of EVT. We hypothesize that uNK cells play a role in priming these vessels to aid subsequent colonization by EVT. We are currently investigating whether soluble factors produced by uNK cells can:

• alter vascular SMC phenotype in the spiral arteries
• induce SMC dedifferentiation
• disrupt SMC alignment and cell-cell adhesions within the arterial wall
• initiate remodelling of the extracellular matrix

Development of vascular homing peptides as a drug delivery system in pregnancy

Suboptimal development in utero remains a problem despite advances in antenatal care. Development of drugs for use in pregnancy is severely lacking as the pharmaceutical industry considers pregnant women to be a high risk cohort. This has created a drug drought in obstetrics and has left clinicians reliant on early delivery and neonatal intensive care.

The ability to deliver pharmaceuticals to the materno-fetal interface offers two broad prospects: acute treatment to extend time in utero and offset early delivery, and intervention early in gestation to prevent later fetal pathology. Development of a strategy to deliver pharmaceuticals to the uterus or placenta will reduce the risks and side effects associated with systemic administration of drugs in pregnancy.

In collaboration with Erkki Ruoslahti at Sanford Burnham Medical Research Institute, I have identified novel homing peptides that bind to the placenta or the endothelium of the uterine spiral arteries. These will be used to develop a targeted drug delivery system suitable for use in pregnancy.

Cell and tissue culture; primary cell isolation; microdissection; immunohistochemistry; proliferation, viability and apoptosis assays; cell cycle analysis; protease activity assays; ELISA; flow cytometry; pressure myography; fluorescence, timelapse and confocal microscopy; RNA interference; immunoprecipitation; western blotting; qRT-PCR; LDL isolation and oxidation; HPLC; bacterial culture; phage display.

I obtained my undergraduate degree in Pathobiology (1999) and PhD (2003) from the University of Reading. During my PhD I studied how cell death in the arterial wall contributed to the development of atherosclerosis, focusing on the cytotoxicity of oxidised lipids and the protective effects of antioxidants. This work was performed in the laboratory of Dr David Leake, in collaboration with Professor Giovanni Mann at King's College London. I then accepted a postdoctoral position in the Maternal and Fetal Health Research Group at the University of Manchester to study the mechanisms of spiral artery remodelling during pregnancy.

My initial studies focussed on the interactions between invasive trophoblast cells derived from the placenta, and vascular smooth muscle cells (SMC) in the uterine spiral arteries. I demonstrated that trophoblasts can induce apoptosis of SMC, and studied the apoptotic signalling pathways employed. I also studied how SMC- and trophoblast-derived matrix metalloproteinases (MMP) cooperate to degrade elastin fibres within the arterial wall during the remodelling process. This research inspired numerous spin-off projects: I have investigated the role of heparanase in trophoblast invasion,  the effect of plasma from women with pre-eclampsia on trophoblast invasion, how nitric oxide may regulated MMP activity at the leading edge of migrating cells and the contribution of uterine natural killer cells to spiral artery remodelling in pregnancy.

In 2010 I was awarded a BBSRC David Phillips Fellowship to develop the use of vascular homing peptides as a targeted drug delivery system in pregnancy.

• BSc (Hons) Pathobiology (I), University of Reading, 1999
• PhD, University of Reading and King's College London, 2003

Professor John Aplin, Dr Melissa Westwood, Dr Ian Crocker, Dr Jenny Myers
Maternal and Fetal Health Research Group, School of Medical and Human Sciences, University of Manchester, UK

Professor Guy Whitley and Dr Judith Cartwright
Division of Basic Medical Sciences, St. George's University of London, UK

Dr Judith Bulmer and Dr Gendie Lash
School of Surgical and Reproductive Sciences, University of Newcastle, UK

Professor Erkki Ruoslahti 
Sanford Burnham Medical Research Insitiute, CA, USA