Placentation & Trophoblast II Flashcards
If the trophoblasts fail to invadeor to remodel the spiral arteries, this can lead to..
important pregnancy complications:
Pre-eclampsia
Fetal growth restriction
Early pregnancy loss
These often have an element that can be summarised as placental insufficiency
Why are problems with trophoblasts important to identify?
These diseases are major causes of maternal and fetal morbidity and mortality
They are diagnosed late in gestation with maternal hypertension
Pathology however is established in the first trimester
Affects 2-5% of all pregnancies
The consequences of placental insufficiency for both the mother and child extends beyond the pregnancy
Mother of a pre-eclamptic pregnancy (within 10-15 yrs)
4x more likely to develop hypertension within 15yrs
2x as more likely to develop ischemic heart disease and stroke
Children develop hypertension
2x more likely to have a stroke
Pre-eclampsia is associated with FGR (fetal growth restriction) and prematurity
Low birth weight is linked to diseases such as type 2 diabetes
This has a High cost to health system
3 million patients in UK
15 million in the USA
What is pre-eclampsia?
condition that causes high blood pressure during pregnancy and after labour. It can be serious if not treated.
Possible causes of poor placental perfusion
Poor trophoblasts invasion
Failure to interact with the maternal spiral artery
Difficulties in studying the mechanisms important in human pregnancy
Animal models:
Mouse
Good for:
Trophoblast differentiation
Not good for:
Cell-cell interactions
Trophoblast invasion (shallow)
SA remodelling (different cells involved)
Three trophoblast cell layers vs one in humans
Rat
Good for:
Maternal syndrome
The great apes are the only exception, they are the best model for human pregnancy, there is evidence to suggest that trophoblast invasion takes place to a similar extent and the remodelling of the spiral arteries follows a similar pattern seen to that as in human pregnancy’s.
BUT there are ethical issues
Difficulties in studying pre-eclampsia human pregnancy
Human tissue is only available at two points:
Studies on term placentae
BUT Organ at the end of its functional life
So has Terminally differentiated
However they are good for transport studies
It is also good for comparing the responses of cells from different pregnancy disorders at term.
First trimester most appropriate (following terminations of pregnancy)
BUT are of limited availability – legal reasons
Main issue is that the pregnancy outcome not known
Legal and ethical issues
Pre-eclampsia can be broke down into two phases:
Maternal phase
Endothelial dysfunction
Hypertension
Placental phase
Placental insufficiency and
poor spiral artery remodelling
The issue with studying placental changes in pre-eclampsia is that diagnosis of the syndrome takes place relatively late in gestation. Therefore it comes at a point beyond which the initial changes may be taking place.
First trimester studies of pregnancies with spiral artery related pathologies
To overcome this, researchers have adopted an approach called Uterine artery Doppler Ultrasound scanning.
This process is used later on in pregnancy to diagnose pre-eclampsia.
But in the first trimester it can be used to determine the uterine artery resistance.
A pregnancy with a high uterine artery resistance = has an increased chance of developing abnormally
If a pregnancy has a normal uterine artery resistance = the pregnancy is most likely to develop without any complications.
Has been done on 10,000 pregnancies, it was determined that:
A normal uterine artery resistance only resulted in 5% of pregnancies developing an issue (eg PE/FGR/stillbirth risk). And under 3% were at risk from developing PE
BUT if there was a high uterine artery resistance in the 1st trimester, then there is a 15% chance of developing PE and a 24% risk of PE/FGR/stillbirth risk.
So there is a 5 fold increase in pregnancies with a high uterine artery resistance in the first trimester.
High RI group -> decreased endovascular trophoblast invasion and artery plugging
Not all high resistant pregnancies develop pregnancy complications – Why?
Examples of Georges studies, looking at most and least likely group to develop pre-eclampsia:
High-RI EVT are less invasive
Can be assessed by looking at spiral artery plugging.
In the first trimester, trophoblasts plug the spiral artery and prevent maternal blood from entering the intervillous space.
This is a normal occurrence. So… the greater the degree of plugging = the more likely the pregnancy will be normal.
If you take material from high resistance index and normal RI, and you look for trophoblast plugging, you can see that there is a significant decrease in the extent of spiral arteries that are plugged:
This suggests that high resistance pregnancies are less invasive than normal pregnancies.
This can be supported by direct assessment of the ability of EVT to invade/migrate from the placental tissue
Study looked at the extent of the EVT outgrowth area in both high and normal resistance index pregnancies.
There is a significant reduction in the ability of the EVT cells to migrate out.
So if a trophoblast is unable to migrate or invade into the decidua, then it is less likely to be able to remodel the maternal spiral artery.
High-RI EVT are more sensitive to apoptotic stimuli
One theory is that they fail to invade and remodel the spiral artery because they undergo apoptosis before they reach the vessel.
Trophoblasts express both the receptor and the ligand for a number of apoptotic inducing molecules:
TNF, FasL or sFasL and TNF-related apoptosis-inducing ligand (TRAIL)
Although placental cell apoptosis is a normal part of placental development and increases after week 40 It has been show that apoptosis is Exaggerated in placental disease such as pre-eclampsia (PE) and fetal growth restriction (FGR)
EVT are resistant to apoptotic stimulation
The study isolated EVTs and induced apoptosis, and follow with time lapse microscopy.
Can create a kinetics curve
There is an increase in resistance to apoptotic stimuli in high RI pregnancies.
AKA high risk pregnancies are more sensitive to apoptotic stimuli than normal resistance pregnancies.
There a correlation between resistance and sensitive to apoptosis
Sensitisation of first trimester EVT by inhibition of NO synthesis
A failure to synthesise NO has been proposed for pregnancies suffering with pre-eclampsia.
L-NAME is an inhibitor of NO synthases
When looking at the induction of apoptosis in the presence of L-NAME, there is some degree of apoptosis.
When looking at the normal inducers of apoptosis present within the placenta: Fas, TNFa and TRAIL, there is not any significant apoptotic events taking place.
BUT if you combine the L-NAME (NO synthesis inhibitor) with each of the stimulants, there is a significant increase in the levels of apoptosis.
High risk & normal resistance group
In the high risk preganacy group, adding L-NAME will have no significant effect
BUT adding NO donor may reduce the sensitivity of these cells to apoptosis:
There is no change by inhibiting NO
BUT there is an increase in the resistance to apoptosis if you provide an NO donor, suggesting that the NO donor is overcoming the pathways that are inducing apoptosis.
In normal resistance group: inhibiting NO, increases the sensitivity to apoptosis.
This suggests that in the pregnancies from the high risk group there may be either an abnormality in the ability to produce NO or to respond to it.
