Lecture 10: Preeclampsia – Placental and Vascular Origins Flashcards
When is development of maternal blood supply to placenta complete?
End of 1st trimester - 12-13 weeks
What organs does the placenta substitute for?
Lungs, kidney, GIT
What are the vascular components of the placenta and what is contained in these?
Fetal - fetal arteries and veins in chorionic plate
Maternal - endometrial arteries and veins
What happens at the metal-maternal interface?
Umbilical arteries and veins move between mother and fetus
What happens to cytotrophoblasts in normal placental development?
Cytotrophoblast cells invade maternal spiral arteries and go from an epithelial to endothelial phenotype, allowing spiral arteries to enlarge to increase blood flow
What do invading trophoblast cells replace?
Endothelial cells and smooth muscle cells
How do uterine spiral arteries change in pregnancy?
- Loss of vascular smooth muscle
- Breakdown extracellular matrix
- Loss of endothelial cells
- Wider arteries
What happens if there is inadequate remodelling of the spiral arteries?
Abnormal placental development and reduced placental perfusion
What is preeclampsia and what are the features?
Pregnancy specific CVD characterised by hypertension >20 weeks gestation and excess serum proteins in urine (>300mg – proteinuria), general oedema
What % of Australian pregnancies are affected by preeclampsia?
5-8%
When do the symptoms of preeclampsia present?
Late in pregnancy (3rd trimester) – need hospitalisation
What happens in eclampsia?
Seizures, coma
What is the treatment for preeclampsia?
Early delivery - need to remove placenta
What happens to babies born to preeclamptic mothers?
Low birth weight and increased risk of adult disease
Where does preeclampsia begin and end?
Placenta to maternal edothelium, causing endothelial dysfunction
What things are thought to contribute to placental dysfunction?
Immune cells, genetic factors, placental oxidative stress and antibodies thought to cause placental dysfunction and hypoxia - releases factors that cause endothelial damage in organs and complications
What things characterise placental dysfunction?
- Abnormal vascular adaptations
- Inadequate trophoblast invasion
- Abnormal spiral artery remodelling
What are the abnormal changes to spiral arteries in preeclampsia?
- Invasion is shallow
- Cytotrophoblasts fail to adopt invasive endothelial phenotype
- Vascular smooth muscle intact
- Arteries remain small, resistance vessels – blood flow and placental perfusion reduced
What is the role of VEGF?
Angiogenesis and vascular relaxation
How does sFlt affect blood vessels and VEGF?
Binds to VEGF and prevents relaxation action - stiffer vessels
When do sFlt levels rise?
Towards end of pregnancy (2 fold increase in preeclamptic women)
When are increases in sFlt detected and when do high levels indicate risk of preeclampsia?
Detected 5-8 weeks before development of preeclampsia, and high levels at 25-32 weeks pose high risk for preeclampsia
What did treatment with sFlt cause?
Increased MAP, proteinuria, endothelial dysfunction
How does sEng change with preeclampsia?
Increased levels in serum and placenta
How does COMT1 change with preeclampsia?
Decreases
What happens to 2-ME during normal pregnancy/preeclampsia?
Increases in normal pregnancy
Levels are low in preeclampsia at 22-29 weeks (low COMT expression)
What happens if you knockout CMOT1?
- Significant increase in sFlt
- Diminished uterine arteries
What happens if COMT1 is present and woman is treated with 2-ME?
sFlt levels returned to normal (2-ME reduces COMT1)
When is relaxin a predictor of preeclampsia?
Low circulating relaxin during first 13 weeks of gestation are a strong predictor of preeclampsia – 7 times more likely to develop preeclampsia
What happens when there is a knockout of relaxin?
- Increase creatinine levels, proteinuria
- Reduction in fetal weight
What does relaxin treatment do?
Restores normal pregnancy vasodilatory phenotype in human arteries from women with preeclampsia
What are the actions of relaxin?
- Increase vasodilation (renal, mesenteric, uterine)
- Increase NO pathway
- Increase vasodilator sensitivity and reduce vasoconstrictor sensitivity
- Decrease stiffness (renal, mesenteric)
What does renin do in pregnancy?
Maintains endothelial function and remodels systemic and uterine vasculature
