The placenta, a pancake shaped organ made of cells from the mother and fetus and crisscrossed by blood vessels shuttling nutrients and other important cargo, is the linchpin of fetal development in the womb for humans and all placental mammals (eutherians). Yet, how nutrient supply through the placenta matches the growing demands of a fetus is unclear.
Using genetically engineered mice, a new study led by scientists at the University of Cambridge shows a gene called IGF2 (insulin-like growth factor 2) expressed in the fetus and cells lining the blood vessels of the placenta is needed for the growth of the placenta during late pregnancy.
The authors have identified a new molecular pathway through IGF2 and its receptor, IGF2R that promote cell division of blood vessels and surrounding placental cells (trophoblast) and mediate the growth of the placental vascular tree to match the needs of the fetus.
The new findings are reported in an article published in the journal Developmental Cell on December 27, titled,”The Imprinted Igf2-Igf2r Axis is Critical for Matching Placental Microvasculature Expansion to Fetal Growth.” Insights from the study may help develop ways of monitoring and maintaining IGF2 levels in the fetus to promote normal placental and fetal growth.
The authors note, “Our study reveals a direct role for the imprinted Igf2-Igf2r axis on matching placental development to fetal growth and establishes the principle that hormone-like signals from the fetus play important roles in controlling placental microvasculature and trophoblast morphogenesis.”
The authors show the genes for IGF2 and its receptor are imprinted—a process by which molecular switches on the genes identify their parental origin and can turn the genes on or off. The copy of the IGF2 gene inherited from the father is active whereas the copy of IGF2R inherited from the mother is active, resulting in a tug-of-war of IGF2 mediated signaling in the placenta.
“One theory about imprinted genes is that paternally-expressed genes are greedy and selfish. They want to extract the most resources from the mother. But maternally expressed genes act as countermeasures to balance these demands,” said senior author of the paper, Miguel Constância, PhD, a lecturer in reproductive biology at the department of obstetrics and gynaecology at the University of Cambridge, U.K. “In our study, the father’s gene drives the fetus’s demands for larger blood vessels and more nutrients, while the mother’s gene in the placenta tries to control how much nourishment she provides. There’s a tug-of-war taking place, a battle of the sexes at the level of the genome.”
For every 100 babies born, 10 to 15 babies grow poorly in the womb—a condition called intrauterine growth restriction (IUGR)—leading to a slew of health effects in childhood and adulthood. IUGR is strongly linked to a poor development of the placental vascular architecture, that must expand dramatically to nearly 200 miles of blood vessels at birth, to accommodate the growing fetus during late pregnancy.
“As it grows in the womb, the fetus needs food from its mum, and healthy blood vessels in the placenta are essential to help it get the correct amount of nutrients it needs,” said Ionel Sandovici, PhD, a research associate at the department of obstetrics and gynaecology at the University of Cambridge, U.K. and first author of the paper. “We’ve identified one way that the fetus uses to communicate with the placenta to prompt the correct expansion of these blood vessels. When this communication breaks down, the blood vessels don’t develop properly, and the baby will struggle to get all the food it needs.”
The researchers found the expansion of the labyrinth of blood vessels in the mouse placenta is linked to an increase in IGF2 signals from the fetus. In humans, too much IGF2 is associated with too much fetal growth, while not enough IGF2 is associated with too little fetal growth. Both scenarios pose higher risk of developing diabetes and heart disease as adults and increase risk of complications and even death during birth.
“We’ve known for some time that IGF2 promotes the growth of the organs where it is produced. In this study, we’ve shown that IGF2 also acts like a classical hormone – it’s produced by the fetus, goes into the fetal blood, through the umbilical cord and to the placenta, where it acts,” says Sandovici.
The findings offer insights on how the fetus, placenta and mother communicate during pregnancy and reveal a tug-of-war between maternal and paternal genes that may help explain why some babies grow poorly in the womb.