Research Implicates Enzyme in the Pathogenesis of Preeclampsia

Researchers have identified an enzyme that is overexpressed in women with preeclampsia, possibly contributing to the development of this condition, according to a new study conducted in Germany.¹

Tissue samples from 25 women with preeclampsia and 23 healthy controls were analyzed using microarray technology. The tissue samples from the women with preeclampsia were from hospitals in Finland, Norway, Austria, and the United States. Researchers found that cytochrome P450 subfamily 2J polypeptide 2 (CYP2J2) enzyme levels were unusually high in placental cells and the decidua (uterine lining) in women with preeclampsia in the second and third trimester compared with controls. CYP2J2 is involved in the production of metabolites called epoxyeicosatrienoic acids (EETs), which function to regulate blood pressure among other things.

The researchers discovered that trophoblasts, which are fetal cells that migrate from the placenta to the deciduas, produce the CYP2J2 enzyme. Trophoblasts help ensure sufficient fetal nutrition by contributing to spiral-artery remodeling. However, the researchers discovered that EETs activate a substance that prevents the trophoblasts from growing deeply enough into the decidua, which disrupts the remodeling process.^1,2 Thus, the fetus is receiving insufficient nutrients, which leads to preeclampsia.

EETs generally are thought to have only beneficial effects on the cardiovascular system. Inhibiting the CYP2J2 enzyme in pregnant rats, which subsequently inhibits EET production, causes hypertension and kidney failure.² The researchers demonstrated that cyclooxygenase can alter EETs in such a way that vasoconstriction occurs, causing hypertension. Essentially, “EETs that normally lower blood pressure can evidently produce metabolites that cause blood pressure to rise in preeclampsia,” explain the researchers. Interestingly, when cyclooxygenase was inhibited in the pregnant animals, the EETs were not converted further and the blood pressure did not increase.

“This work shows that the increased production of EET in the placenta and the conversion via cyclooxygenase into hormones that increase blood pressure both favor the development of preeclampsia,” explained Florian Herse and Ralf Dechend, the lead researchers.²

A possible reason for why there is an increased production of CYP2J2, and thus more EET, in women with preeclampsia is the presence of tumor necrosis factor alpha (TNF-alpha), suggest the researchers.^1,2 Released early in pregnancy whenever placental blood flow is too low, TNF-alpha promotes the production of CYP2J2 and EET in the placenta. This reaction, although useful in other tissues, causes a vicious cycle in the placenta by boosting production of CYP2J2 and EET, which causes trophoblasts to not grow as deeply into the decidua and disturbed uteroplacental remodeling, disrupting the blood flow through the placenta and, consequently, the fetus. The mothers become hypertensive and, under these conditions, EETs are converted in such a way that causes maternal blood pressure to continuously increase.

Pertinent Points:
- This new research implicates a previously unknown mechanism for preeclampsia.
- The discovery may contribute to a better understanding of the processes and causes of preeclampsia and possibly help in the eventual development of a therapy.

References:

1. Herse F, LaMarca B, Hubel CA, et al. CYP2J22 expression and circulating epoxyeicosatrienoic metabolites in preeclampsia. Circulation. 2012 Nov 15. [Epub ahead of print.]
2. New risk factor identified for high blood pressure during pregnancy. Available at: http://www.mdc-berlin.de/en/news/2012/20121122-new_risk_factor_identified_for_high_blood_/index.html. Accessed December 3, 2012.