Molecular biology quest to reduce maternal deaths

3 January 2020

Dr Theresa Nga Ling Ko (Croucher Fellowship 2006) is on a mission to understand the mechanisms behind a devastating complication in pregnancy that each year claims the lives of more than 60,000 women.

Ko, an Assistant Professor at The University of Vermont, Larner College of Medicine, Department of Obstetrics, Gynaecology and Reproductive Sciences, is unravelling the mysteries involved in the process of uterine vascular remodelling during pregnancy, a necessary step to improve the clinical treatment of preeclampsia and other pregnancy complications asssociated with hypertension.

Preeclampsia is a pregnancy complication characterised by a rapid increase in blood pressure and signs of damage to other organ systems, most often the liver and kidneys. It usually begins after 20 weeks of pregnancy and can lead to seizure, stroke, multiple organ failure, and death of the mother, as well as the baby.

Preeclampsia and eclampsia – the latter is when seizures occur – account for approximately 63,000 maternal deaths annually worldwide. A study from the US Centers for Disease Control and Prevention (CDC) found the overall fatality rate from the condition to be 6.4 per 10,000 cases at delivery.

“This is a very important area of research because preeclampsia is a mysterious, multi-factorial condition,” said Ko. Some of her research has been funded by the Preeclampsia Foundation and at their Champion for Change Summit in 2018 she met patient advocates and survivors of the condition.

“It was very traumatic for them. They were healthy and expecting a happy pregnancy but after 20 weeks things start to go wrong, and some survivors lost their babies or had pre-term babies with major complications,” she said.

Despite the seriousness of the condition, which has no cure except delivery of the baby and placenta and medication to alleviate the symptoms and prevent seizure, relatively little has been known about its causes.

Several factors are involved, including the blood vessel growth and remodelling for sending blood to the placenta, the organ that nourishes the foetus throughout pregnancy. The physiology of maternal uterine vascular adaptation during pregnancy is a mechanism essential for facilitating the regulating of uteroplacental blood flow (UPBF) required for healthy foetal development.

“I was fascinated and drawn into the vascular adaption and uterine circulation and how it remodels during pregnancy – it’s such a complicated system,” said Ko, a molecular biologist who was introduced to this subject when she joined the lab of Professor George Osol in the Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont, in 2015.

Initially, Ko was just keen to return to the lab environment after a four-year break from research. The topic was a departure from her previous successful work at the Pasteur Lab in Paris, for which she had been awarded a Croucher Fellowship in 2006. That and her subsequent research at the University of Kansas had focused on the pathophysiology of adult T-cell leukaemia and lymphoma caused by the human T-cell leukaemia virus (HTLV).

Despite entering a different area of research, Ko’s background in molecular biology – which began as an undergraduate at the Chinese University of Hong Kong – and experience of medical research projects proved to be of great benefit, paving the way for her to take on an increasingly influential role within the research team.

In one of three ground-breaking projects, Ko and her team looked at Piezo1 – a shear-stress sensitive cation channel discovered in 2010 – and its specific role within maternal uterine circulation.

By using a preeclamptic model in rats, Ko examined how this recently discovered

mechanosensor is regulated during pregnancy. She explored the mechanisms by which it senses

the change of uteroplacental blood flow (UPBF) and transduces this information into biological signals that lead to adaptations of uterine vessels during normal versus preeclamptic pregnancy.

“As blood flows through the vessel, it can sense this flow (i.e. shear stress) and convert these mechanical stimuli to biological signals so that the body can adapt to the needs of the growing foetus. As more blood flows, it sends more signals to increase the size of the vessel to maintain the optimum blood pressure and thus avoid hypertension,” she explained.

Piezo 1 had been studied extensively in the context of brain and lung functioning but this was the first time it was discovered in uterine blood circulation. According to Ko, the expression of the channel is up-regulated in pregnancy. This means that Piezo 1 has a specific functional role to help remodel the blood vessels to regulate blood pressure, suggesting that it may play an important role in gestational regulation of uteroplacental blood flow.

“If we can understand the signalling pathways in uterine vascular remodelling, then we can develop drugs targeting this mechanism to improve the remodelling process,” Ko said.

She explained that Piezo 1 was a hot topic because of its presence in diverse biological processes. Recent studies have shown that approximately one-third of African people possess the same mutation of this mechanosensory channel, which slows the activation of the channel. It has been suggested that it may account for a higher prevalence of cardiovascular diseases, and maybe preeclampsia, in women from African nations. This is something that Ko would like to investigate further.

In another published research project, Ko and her team examined venoarterial signalling (VAS) in gestational uterine adaptation. While research had focused more on the arteries, Ko was interested to know about the importance of veins in uterine vascular remodelling.

In the uterus, the vein and the artery are next to each other. Her team developed a novel animal model with a surgical approach. They discovered that the removal of a segment of the uterine vein next to the uterine artery results in 50 per cent less arterial remodelling during pregnancy. That means the signals sent from the foetus and/or placenta (the fetoplacental unit) to the postplacental uterine veins are transferred across to the preplacental arteries and then stimulate the vessel remodelling.

This study provided the first in vivo evidence for the importance of venous influences on arterial growth within the uteroplacental circulation.

“I am very interested in the veins and it’s a neglected area of research,” she said.

Having been promoted to Assistant Professor in July 2019, Ko will assume responsibility for all aspects of research after the retirement of Professor Osol, whom she describes as the “ideal mentor”. She aims to secure funding for more research into uterine vascular remodelling and has a longer-term goal to set up collaborative projects to investigate the potential of Traditional Chinese Medicine (which she specialised in during her PhD studies) being incorporated in the treatment of conditions such as preeclampsia.

“There are still lots of new things to learn,” she said, hoping that her unorthodox career path provides encouragement to other scientists that it is possible to change track or take a complete break from research and still achieve significant results.

Dr Theresa Nga Ling Ko completed her bachelor and master’s degrees in biology at The Chinese University of Hong Kong (CUHK). After gaining her PhD in Pharmacology in 2005 from CUHK, she worked as a researcher for a pharmaceutical company in Hong Kong. In 2006, she was awarded a Croucher Fellowship to undertake post-doctoral studies at the Unit of Epidemiology and Physiopathology of Oncogenic Viruses in the Pasteur Institute, Paris, working with Dr Antoine Gessain and Dr Renaud Mahieux to study the pathophysiology of adult T-cell leukaemia/lymphoma caused by the human T-cell leukaemia virus (HTLV). From 2009 to 2011, she continued her research on HTLV viruses at the University of Kansas Medical Center, USA, with Dr Christophe Nicot. After a break from research she joined The University of Vermont, Larner College of Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences in July 2015, and was promoted to Assistant Professor in July 2019.

To view Dr Ko’s Croucher profile please click here.