Using laboratory mice, researchers in the US have discovered a possible way that the pregnancy disorder pre-eclampsia may be triggered by the COMT gene, already known to play a role in schizophrenia.
The study also suggests that the steroid molecule 2-ME could be a useful marker for diagnosing the dangerous pregnancy condition, and serve as a basis for treatment.
The findings are published in the 11th May advance online issue of the journal Nature and the research was led by investigators at Beth Israel Deaconess Medical Center (BIDMC), a teaching hospital of Harvard Medical School in Boston, and colleagues from other research centres.
Pre-eclampsia affects about 5 per cent of pregnancy women worldwide and is a leading cause of death of mothers and newborns. Its symptoms include high blood pressure, swelling or edema, and proteinuria (too much protein in the urine).
Another key symptom of pre-eclampsia is hypoxia, or shortage of oxygen, to the placenta, and it was this that spurred senior study author Dr Raghu Kalluri and colleagues to look for genes that might control hypoxia.
Kalluri, who is Chief of the Division of Matrix Biology at BIDMC and Professor of Medicine at Harvard Medical School, said seeing pregnant women with pre-eclampsia in the clinic inspired him to dedicate himself, and the efforts of his team, to finding the likely genetic causes of the condition.
“During pregnancy, hypoxia is associated with the formation of new blood vessels,” explained Kalluri.
During the first trimester, when the fetus is developing rapidly, hypoxia levels are high, he said, and later on, they should come down again as fetal blood vessel development slows down. But, in women with pre-eclampsia, this does not happen, and they continue to be hypoxic into their third trimester, he said.
Kalluri and colleagues focussed on an enzyme called catechol-O-methyltransferase, or COMT, which normally inactivates catecholamines, a class of neurotransmitters, and is also known to play a role in schizophrenia.
They already knew that COMT helps to break down estrogen into 2-methoxyestradiol or 2-ME, a metabolite that stops a protein that induces hypoxia, and they wondered if perhaps it was not working properly in women with pre-eclampsia. They were able to partly verify their hunch because when they tested pregnant women with pre-eclampsia, they found reduced levels of both COMT and 2-ME.
The next step therefore, was to see if they could induce pre-eclampsia by triggering a deficiency in COMT using genetic engineering. Obviously they couldn’t do this in humans, and mice are the next best thing because they have many similar genes and enzymes.
The researchers bred a group of mice lacking the COMT gene, and as predicted, they failed to synthesize 2-ME. When the mice were 14 weeks pregnant, which is equivalent to the start of the third trimester in humans, they started to show protein in their urine, developed high blood pressure, and had hypoxia-like problems in the development of placental blood vessels, in other words, all the hallmarks of pre-eclampsia.
The mice also gave birth about a day earlier and there was a higher level of stillbirths, compared to normal mice, but once they gave birth, the mice returned to normal health.
Speculating on their findings, Kalluri suggested that the loss of 2-ME probably led to a cascade of events that ended up as pre-eclampsia.
“Disruption of COMT/2-ME led to elevated hypoxia, leading to angiogenic dysfunction and placental insufficiency, which then results in a further decrease in 2-ME levels,” he explained.
The final clinch came when they then gave 2-ME to the mice, which reversed their pre-eclampsia-like symptoms.
Kelluri suggested that perhaps many of the factors found in recent years to be too high or too low in women with pre-eclampsia could be regulated by 2-ME.
This implies that the “action of COMT is central to proper vascular function in the placenta,” added Kalluri.
“This study offers the possibility of screening for COMT gene defects in pregnant women to predict preeclampsia,” he noted.
“Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia.”
Keizo Kanasaki, Kristin Palmsten, Hikaru Sugimoto, Shakil Ahmad, Yuki Hamano, Liang Xie, Samuel Parry, Hellmut G. Augustin, Vincent H. Gattone, Judah Folkman, Jerome F. Strauss & Raghu Kalluri
Nature advance online publication 11 May 2008.
DOI:10.1038/nature06951.
Source: journal abstract, Beth Israel Deaconess Medical Center press release.
Written by: Catharine Paddock, PhD