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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.
Pathogenesis of Preeclampsia
“Disease of theories"
Poor Placentation and Preeclampsia
Placental Vascular Pathology in Preeclampsia
“Placental vascular insufficiency”
Normal
Preeclampsia
Glomerular Endotheliosis
Control Preeclampsia
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
EPO and sVEGFR1 (sFlt1) in Amniotic Fluid
Vuorela et al, 2000
Annual Reviews
Plasma sFlt1 in Pregnancy
Levine et al 2004
In vivo Effects of sFlt1
Maynard et al, 2003
Cytotrophoblast Response to Hypoxia
Nagamatsu et al 2004
Utero-placental Ischemia in Primates
Makris et al, KI 2007
Placental perfusion reduced by ~ 30-50%
Utero-placental Ischemia in Primates
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
Oxygen Sensing
HIF1α
VEGF
αα
α
2-Methoxyestradiol Inhibits EC Growth, Angiogenesis and Tumor Growth
Fibroblats
EC
Fotsis et al, 1994
2-Methoxyestradiol
CYP450
COMT
- pM in control Plasma - nM in plasma of pregnancy - μM in ovaries & tissues with high [estradiol]
Catechol-O-methyl Transferase
2-Methoxyestradiol Inhibits HIF1α
Mabjessh et al 2003
α-tubulinHIF1α
2-Methoxyestradiol and HIF
COMT-/-
COMT in Placenta
Placenta
Placenta
+/+ -/- +/+
-/- -/- + 2ME -/- +2ME
2/56
32/64
Eosin+ deposition Thrombosis arterial lumen
Placenta
IgM
vWF
+ME
Blood Pressure
Non-pregnant Blood Pressure
Proteinuria
Kidney
WT WT+Ro41-0960 COMT-/- COMT-/- + ME
EC swelling, detachment and vacualization (“endotheliosis”)
Placental Hypoxia
WT COMT-/- COMT-/- + ME
WT-/--/- + ME
Placental HIF1α
WT COMT-/- COMT-/- + ME
SP, spongiotrophoblast layer
Placental HIF1α
WT
-/-
-/- + ME
Plasma sFLT-1
Plasma Catecholamines
WT + MAO inhibitor
Placental Vasodilators
RT-PCR
Western
Inflammatory Mediators
Decidual IFN-γ and NK Cells
IFN-γ
NK CellsNKp46+CD3-
2-Methoxyestradiol Effects in Cytotrophoblast Cell Line
Tubulin
microtubule disruption
Human Pregnancy
2-Methoxyestradiol and COMT in Human Pregnancy
Plasma 2-ME
Placental COMT
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
Proposed Model
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