Placentation & the Trophoblast II Flashcards
Why are we interested in trophoblast invasion? (4)
Failed/inadequate remodelling leads to common pregnancy complication:
Pre-eclampsia
Fetal growth restriction
Early pregnancy loss
What are the long term effects of failed remodelling? (9)
- Major cause of maternal + fetal morbidity/mortality
- Diagnosed late in gestation with maternal
hypertension - Pathology established in the first trimester
- Affects 2-5% of pregnancies
- Mother (within 10-15 yrs)
4x hypertension
2x ischemic heart disease and stroke - Children develop hypertension -2x likely to have a stroke
- PE is associated with FGR and prematurity
- Low birth weight is linked to diseases such as
type 2 diabetes - High cost to health system 3 million patients in UK
15 million in the USA
what are some potential causes of poor placental perfusion? (2)
-Poor trophoblasts invasion
-Failure to interact with the maternal spiral artery
What are the difficulties in studying the mechanisms important in human
pregnancy? (- of animal models) (6)
Animal models don’t exhibit same pregnancy complications as humans except great apes
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
what is the best model for human pregnancy and why? (4)
Great apes - evi shows trophoblast invasion takes place to a similar extent + remodelling of spiral arteries follow a similar pattern as humans
- bristol zoo: gorilla suffering pre-eclampsia = c section
what are the concerns w/ performing studies on great apes?
ethical issues
What are the difficulties in studying pre-eclampsia human pregnancy? (6)
Humans Studies can only take place w/ retrieval of tissues at 2 point: at birth or in the 1st tri. (in placenta) terminations
On term placentae:
– Organ at the end of its functional life (= starts to deteriorate)
– Terminally differentiated (= v little that can be achieved from them)
– Good for transport studies
First trimester most appropriate:
– Limited availability
– Pregnancy outcome not known (2 phases of pre-eclampsia- diagnosis takes place late in gestation/ beyond the initial changes )
– Legal and ethical issues
What are the 2 phases of pre-eclampisa?
Placental phase : Placental insufficiency and poor spiral artery remodelling
Maternal phase: Endothelial dysfunction hypertension
Overcoming the issues of placental pre-eclampsia studies - (SGUL) : Uterine Artery Doppler Ultrasound (4)
(used later in pregnancy to diagnose pre-eclampsia)
but decided to use in 1st trim. = detect artery resistance
high artery resistance = inc. chances of abnormal dev. if preg. continues (24% - 15% PE))
normal range = most likely to dev. w/o any complications (5% -2.8% PE)
Not all high resistant pregnancies develop pregnancy complications – Why? - 2 studies SGUL (4)
1) groups most + least likely to dev. preeclampsia - if gone to term (by screening decidua)
- (is there evi. of poor trophoblast inv. migra. ?) - looked at spiral artery plugging : higher plugging = inc. normality rates
= saw decrease in high risk
= high resi. preg. < invasive than normal preg.
2) (study of tropho. migration support this?) - looked at extent of RI outgrowth =
= high resi. = sig. reduc. ability to migrate out
= less likely to/unable to remodel spiral arteries
How else might trophoblasts be affected by preeclampsia vs normal pregnancies?
theory: they fail to invade + remodel because undergo apoptosis before they reach vessel = do Hi express more apoptotic sign.?
do High RI express more apoptotic sign.? (3)
Trophoblasts express:
* TNF, FasL or sFasL and TNF-related apoptosis-inducing ligands (TRAIL)
* + the receptors
- Normal part of placental development increases after week 40
=Exaggerated in placental disease such as pre-eclampsia (PE) and fetal growth restriction (FGR (EVT are resistant to apoptotic stimulation)
induce apop. = create kinetics curves
found increased resistance to apoptosis in normal compared to High RI
Can we find a molecular explanation for High RI + preclampsia apoptosis? - Sensitisation of first trimester EVT by inhibition of NO synthesis (4)
NO reduces apoptosis in preg.
looked at L-name = no chnage
L-name + Fas Ab = high
w/ High RI: increased
w/ norm. RI: increased
= preg. from High RI may have abnorm. to produce and or respond to NO
Summary: (4)
- The symptoms of pre-eclampsia appear late in gestation yet the aetiology is believed to be in the first trimester
- It is presently not possible to identify in the first trimester those pregnancies that will develop pre-eclampsia
- It is possible to identify those at increased risk
- Cells isolated from high risk patients are different from those low or normal risk
