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Preeclampsia
- Hypertension & proteinuria in last trimester of pregnancy
- Complicates 2-3 % pregnancies
- Requires placenta (even if no fetus; hydatidiform pregnancy)
- Remits post-partum
- Placenta is frequently abnormal with ischemic/hypoperfusion lesions
- In severe PE, there is micro-angiopathy and endothelial dysfunction with many target organs potentially involved: liver, kidney, CNS, etc.
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Pathogenesis of Preeclampsia
“Disease of theories"
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Poor Placentation and Preeclampsia
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Placental Vascular Pathology in Preeclampsia
“Placental vascular insufficiency”
Normal
Preeclampsia
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Glomerular Endotheliosis
Control Preeclampsia
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Abnormal Placenta and Placental Factors
- neurokinin B Nature. 2000 Jun 15;405(6788):797-800
- thromboplastin Nature. 1963 Sep 14;199:1105-6
- magnesium deficiency Science. 1983 Jul 22;221(4608):376-8
- adrenomedullin Lancet. 1997 Nov 29;350(9091):1600
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EPO and sVEGFR1 (sFlt1) in Amniotic Fluid
Vuorela et al, 2000
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Annual Reviews
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Plasma sFlt1 in Pregnancy
Levine et al 2004
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In vivo Effects of sFlt1
Maynard et al, 2003
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Cytotrophoblast Response to Hypoxia
Nagamatsu et al 2004
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Utero-placental Ischemia in Primates
Makris et al, KI 2007
Placental perfusion reduced by ~ 30-50%
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Utero-placental Ischemia in Primates
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Preeclampsia
- Increased in some factors that are activated during hypoxia
- Can be induced by reduction of placental blood flow
- Hence, either there is ischemia (with appropriate hypoxicresponse) or there is an abnormality in the hypoxia-regulated response
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Oxygen Sensing
HIF1α
VEGF
αα
α
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2-Methoxyestradiol Inhibits EC Growth, Angiogenesis and Tumor Growth
Fibroblats
EC
Fotsis et al, 1994
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2-Methoxyestradiol
CYP450
COMT
- pM in control Plasma - nM in plasma of pregnancy - μM in ovaries & tissues with high [estradiol]
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Catechol-O-methyl Transferase
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2-Methoxyestradiol Inhibits HIF1α
Mabjessh et al 2003
α-tubulinHIF1α
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2-Methoxyestradiol and HIF
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COMT-/-
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COMT in Placenta
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Placenta
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Placenta
+/+ -/- +/+
-/- -/- + 2ME -/- +2ME
2/56
32/64
Eosin+ deposition Thrombosis arterial lumen
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Placenta
IgM
vWF
+ME
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Blood Pressure
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Non-pregnant Blood Pressure
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Proteinuria
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Kidney
WT WT+Ro41-0960 COMT-/- COMT-/- + ME
EC swelling, detachment and vacualization (“endotheliosis”)
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Placental Hypoxia
WT COMT-/- COMT-/- + ME
WT-/--/- + ME
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Placental HIF1α
WT COMT-/- COMT-/- + ME
SP, spongiotrophoblast layer
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Placental HIF1α
WT
-/-
-/- + ME
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Plasma sFLT-1
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Plasma Catecholamines
WT + MAO inhibitor
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Placental Vasodilators
RT-PCR
Western
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Inflammatory Mediators
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Decidual IFN-γ and NK Cells
IFN-γ
NK CellsNKp46+CD3-
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2-Methoxyestradiol Effects in Cytotrophoblast Cell Line
Tubulin
microtubule disruption
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Human Pregnancy
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2-Methoxyestradiol and COMT in Human Pregnancy
Plasma 2-ME
Placental COMT
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Summary
- 2-methoxyestradiol inhibits HIF1α
- Placenta expresses catechol-O-methyl transferase and 2-ME increases during pregnancy
- COMT KO and COMT inhibitors cause pre-eclampsia
- 2-ME prevents pre-eclampsia in COMT KO mice; thus, PE in these mice its unlikely due to excess catecholamines and vasoconstriction
- Women with PE have low plasma levels of 2-ME and lower COMT protein in their placenta; 2-ME may provide a therapy for pre-eclampsia
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Proposed Model