An animal model of pre-eclampsia

Every year millions of women fall pregnant; but up to 10% of them can develop the condition pre-eclampsia, which is associated with dangerously high blood pressure that can be life-threatening if it’s not managed promptly and appropriately. And although doctors are very good at doing that, we’re still not entirely sure why the condition occurs in the first place; which makes predicting and preventing it that much more difficult. Now, speaking with Chris Smith, MIT scientist Katie Bezold Lamm explains how she has found a way to produce a very similar manifestation in mice, which might give us new clues as to what’s going on…

Katie - The placenta is a specialised organ that only occurs during pregnancy. It's created by the developing baby. It's the site of communication between mom and baby and the site of gas and nutrient exchange for the developing baby.

Chris - How does it actually form?

Katie - So the placenta is formed by invasive cells from the developing fetus that invade into the maternal uterus. These cells locate maternal spiral arteries and replace the underlining endothelium, widening these arteries to increase the amount of blood flow to the placenta, effectively increasing the amount of available nutrients and oxygen for the placenta to deliver to the baby. However, in a certain subset of pregnancies, this invasion of specialised cells called trophoblasts does not occur quite as effectively as it should. The spiral arteries aren't properly remodelled so the amount of blood flow available is drastically decreased. And since these spiral arteries are thinner or the diameter is reduced the mother is at risk for developing high blood pressure in pregnancy which can lead to pre-eclampsia. Additionally, since there is a reduction in the amount of blood flow available the baby is at risk for developing intrauterine growth restriction where the baby is then small for its gestational age.

Chris - It's quite common this isn't it, pre-eclampsia? But do we actually know what causes it?

Katie - Absolutely, pre-eclampsia is very common. But while it is generally understood that pre-eclampsia arises due to shallowly invading trophoblast cells we don't actually know what regulates invasion of these cells and what goes wrong to cause pre-eclampsia. And so we sought to determine the mechanisms that regulate trophoblast invasion. And so we decided to study the inverted formin-2 protein which is responsible for generating invasive structures in cells.

Chris - So what actually is this protein? Where does it come from and how does it act on a cell?

Katie - So inverted formin-2 is actually found in a wide variety of different cell types but what its primary role is in the cell is to maintain the actin's cytoskeleton. It has a unique ability to depolymerise actin filaments. This is important in invasion because cells need to be able to form actin rich protrusions that allow cells to invade.

Chris - Right, so you've got this protein is made in these trophoblast cells that are doing the invading into the maternal arteries and they're expressing heavily this protein which can remodel the skeleton inside the cell which will warp the cells making them change shape and bend and twist and so on. So is your hypothesis then, that this protein is in some way linked to the ability to invade and if it wasn't being expressed correctly or in the right amounts, that might be why invasion fails or doesn't progress far enough down the artery, and that's what causes pre-eclampsia?

Katie - Yes. Our hypothesis was that inverted formin-2 (INF2) is necessary for trophoblast invasion and that loss of inverted formin-2 would reduce spiral artery invasion and lead to pre-eclampsia. So to test this hypothesis we used a culture method of extravillous trophoblasts, in which we've knocked down inverted formin-2 and saw that these cells had a reduced capability of invasion.

Chris - What about in vivo though because it's one thing to do this in a dish it's a very different effect in vivo?

Katie - That's actually a really good question. So to understand the role of inverted formin-2 in vivo, we turned to a knockout mouse model. When we studied the pregnancies of these knockout mice we found that the pregnant mice displayed new-onset high blood pressure late in pregnancy and that it wasn't until they delivered the pups and their placentas that blood pressure returned to normal. Additionally, we looked at the spiral artery remodelling in these INF2 knockout mice and found that there was a significant reduction in the number of spiral arteries in these knockout mice, suggesting that spiral artery remodeling in these mice is reduced. The pups in these INF2 knockout mice were significantly smaller than the wild-type counterparts.

Chris - So basically what you've managed to create is a very, very close mimic of what we see in human pre-eclampsia, because you've got animals that develop high tension, they have intrauterine growth retardation, and all of the other negative consequences go away after the animals give birth which, which is a very strong mimic for what we see in the human condition?

Katie - Yeah, it is a really interesting phenotype that does recapitulate several aspects of pre-eclampsia and intrauterine growth restriction. I do think we are a bit far from thinking about potentially treating preeclampsia but this would provide an interesting method for screening people at increased risk for developing pre-eclampsia.