Placental development, pregnancy complications and long-term health consequences of placental insufficiency

Placental development, pregnancy complications and long-term health consequences of placental insufficiency is a Research Project for the Archived: Implantation and Placental Development Research Group, under the Centre for Reproductive Health.

Project Leader

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The placenta is a highly specialised and pregnancy-specific organ that physically connects the fetus to the mother, functioning as a nutrient and waste exchanger. The placenta implants into the uterine wall and forms extensive vascular connections to receive nutrients, oxygen, antibodies and hormones from the mother’s blood, and also to remove fetal waste. The placenta also produces hormones, growth factors and other proteins to redirect maternal systems to facilitate fetal growth. Any placental abnormalities pose a risk to both the development of the fetus and the wellbeing of the mother.

Since we discovered HtrA3 in the developing placenta in 2003, we became very interested in the mammalian HtrA family proteases and their role in placental development. The first member of HtrA (“high temperature requirement factor A”) was identified in E. coli as a heat shock protein required for high temperature tolerance, hence the name HtrA. To date, four mammalian HtrA proteins (HtrA1-4) have been identified with a range of cellular functions.

Our studies suggest that HtrA proteases are differentially regulated during placental development and pregnancy complications such as preeclampsia, intra-uterine growth restriction and miscarriage. We are now investigating these HtrA proteases, together with a number of other proteins and pathways, in normal placental development and pregnancy complications. One of our major goals is to develop strategies for the early detection and treatment of preeclampsia, a life-threatening disorder of human pregnancy.

We have already established a strong link between HtrA3, placental development, and pregnancy outcomes. HtrA3 is maximally produced in the first trimester when the placenta is developing, and our studies suggest that HtrA3 levels alter during early pregnancy in women who develop preeclampsia later in pregnancy.

Our studies have also established that HtrA1 and HtrA4 play important causal roles in the development of preeclampsia, especially early-onset preeclampsia. Both of these HtrA members are up-regulated in the preeclamptic placentas and secreted into the maternal blood. Our studies suggest that excess circulating HtrAs, particularly HtrA4, have a detrimental impact on endothelial homeostasis.

We also study the long-term health consequences of placental insufficiency and pregnancy diseases for both the mother and baby. We deleted HtrA3 from the mouse genome and found that mothers without HtrA3 can reproduce, but they suffer from placental insufficiency and consequently give birth to growth-restricted babies. Importantly, we discovered that these growth-restricted offspring, regardless of whether they lacked HtrA3 or not, were significantly heavier and had a larger mass of white fat. This study thus reveals that maternal HtrA3 is key to optimising placental development, which has important consequences for the long-term adiposity and wellbeing of the offspring in adulthood. We are continuing to investigate the links between placental insufficiency and long-term health consequences in humans.

Collaborators

Prof Stephen Tong (Mercy Hospital for Women, Melbourne, Australia)
A/Prof Tu’uhe Kaitu’u-Lino (Mercy Hospital for Women, Melbourne, Australia)
Dr Kirsten Palmer (Monash Health, Melbourne, Australia)
Prof Claire Roberts (The University of Adelaide, Adelaide, Australia)
Prof Gus Dekker (The University of Adelaide, Adelaide, Australia)
Prof Jon Hyett (Royal Prince Alfred Hospital, Sydney, Australia)
Dr Louis Lu (CSIRO, Melbourne, Australia)
Dr Mylinh La (CSIRO, Melbourne, Australia)
Prof George Lovrecz (CSIRO, Melbourne, Australia)
Dr Tracy Nero (Bio21, Melbourne, Australia)
Prof Michael Parker (Bio21, Melbourne, Australia)
Dr Qi Chen (University of Auckland, Auckland, New Zealand)
Prof Fabricio Costa (University of Sao Paulo, Sao Paulo, Brazil)
Prof Silja Wessler (University of Salzburg, Austria)