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