 |
|
A new gene trigger for pregnancy disorder identified
May 12, 2008Clues into how preeclampsia may surface in some pregnancies
BOSTON - The COMT gene - known already for its role in schizophrenia - has been found to play a role in preeclampsia, according to a report in today's advance on-line issue of Nature.
Led by researchers at Beth Israel Deaconess Medical Center (BIDMC), the study further suggests that a steroid molecule, 2-ME, may serve as both a diagnostic marker and therapeutic supplement for the treatment of this dangerous pregnancy disorder.
Characterized by hypertension, proteinuria, and edema, preeclampsia affects approximately 5 percent of all pregnancies worldwide, and is a leading cause of maternal and neonatal morbidity. Knowing that placental hypoxia, or oxygen shortage, associated with vascular dysfunction, is a hallmark of the condition, senior author Raghu Kalluri, PhD and his colleagues began by screening for genes that regulate hypoxia.
"Seeing pregnant women with this disease in the clinic inspired me to dedicate our efforts to find likely causative genes that play a role in preeclampsia," says Kalluri.
"During pregnancy, hypoxia is associated with the formation of new blood vessels," explains Kalluri, Chief of the Division of Matrix Biology at BIDMC and Professor of Medicine at Harvard Medical School.
"As a result, during the first trimester of pregnancy, when the fetus is undergoing rapid development, hypoxia levels are high. As the pregnancy progresses, hypoxia levels should naturally come down as fetal blood vessels formation slows." But, he adds, for unknown reasons, patients with preeclampsia remain hypoxic well into their third trimester of pregnancy.
Studies in the Kalluri laboratory revealed an enzyme known as COMT (catechol-O-methyltransferase) in preeclampsia, a gene commonly associated with schizophrenia which, under normal circumstances, inactivates the catecholamine class of neurotransmitters.
"Interestingly, this enzyme contributes to the breakdown of estrogen into 2ME (2-methoxyestradiol), a metabolite that suppresses the activity of hypoxia inducible factor protein," explains Kalluri. "We wondered if, in cases of preeclampsia, COMT was not functioning properly. In support of this hypothesis, we found that COMT levels were deficient and 2-ME levels were lower in pregnant women with preeclampsia."
Next the investigators looked at genetically engineered COMT deficient mice; as predicted, the animals failed to produce 2-ME. At 14 weeks gestation - the presumable equivalent of the beginning of the third trimester in human pregnancy - the animals developed protein leak in the urine, high blood pressure and problems with placental blood vessels associated with decreased oxygen levels.
In addition, the animals delivered a day or so earlier than normal pregnant mice and there was a greater incidence of stillborn pups. However, once the pups were delivered, the health of the mother returned to normal.
"The loss of 2-ME likely sets in motion a cascade of events culminating in preeclampsia," says Kalluri. "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."
In the final portion of the study, the authors administered 2-ME to the mice, resulting in a reversal of preeclampsia-like-symptoms.
"Interestingly, the many diverse factors that have been identified in the recent years as elevated or suppressed in women with preeclampsia are fixed by 2-ME, suggesting that this action of COMT is central to proper vascular function in the placenta," notes Kalluri. "This study offers the possibility of screening for COMT gene defects in pregnant women to predict preeclampsia."
Beth Israel Deaconess Medical Center
"Seeing pregnant women with this disease in the clinic inspired me to dedicate our efforts to find likely causative genes that play a role in preeclampsia," says Kalluri.
"During pregnancy, hypoxia is associated with the formation of new blood vessels," explains Kalluri, Chief of the Division of Matrix Biology at BIDMC and Professor of Medicine at Harvard Medical School.
"As a result, during the first trimester of pregnancy, when the fetus is undergoing rapid development, hypoxia levels are high. As the pregnancy progresses, hypoxia levels should naturally come down as fetal blood vessels formation slows." But, he adds, for unknown reasons, patients with preeclampsia remain hypoxic well into their third trimester of pregnancy.
Studies in the Kalluri laboratory revealed an enzyme known as COMT (catechol-O-methyltransferase) in preeclampsia, a gene commonly associated with schizophrenia which, under normal circumstances, inactivates the catecholamine class of neurotransmitters.
"Interestingly, this enzyme contributes to the breakdown of estrogen into 2ME (2-methoxyestradiol), a metabolite that suppresses the activity of hypoxia inducible factor protein," explains Kalluri. "We wondered if, in cases of preeclampsia, COMT was not functioning properly. In support of this hypothesis, we found that COMT levels were deficient and 2-ME levels were lower in pregnant women with preeclampsia."
Next the investigators looked at genetically engineered COMT deficient mice; as predicted, the animals failed to produce 2-ME. At 14 weeks gestation - the presumable equivalent of the beginning of the third trimester in human pregnancy - the animals developed protein leak in the urine, high blood pressure and problems with placental blood vessels associated with decreased oxygen levels.
In addition, the animals delivered a day or so earlier than normal pregnant mice and there was a greater incidence of stillborn pups. However, once the pups were delivered, the health of the mother returned to normal.
"The loss of 2-ME likely sets in motion a cascade of events culminating in preeclampsia," says Kalluri. "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."
In the final portion of the study, the authors administered 2-ME to the mice, resulting in a reversal of preeclampsia-like-symptoms.
"Interestingly, the many diverse factors that have been identified in the recent years as elevated or suppressed in women with preeclampsia are fixed by 2-ME, suggesting that this action of COMT is central to proper vascular function in the placenta," notes Kalluri. "This study offers the possibility of screening for COMT gene defects in pregnant women to predict preeclampsia."
Beth Israel Deaconess Medical Center
Preeclampsia News and Current Preeclampsia Events RSSMaternal deaths following cesarean delivery can be reduced
Maternal death rates have remained constant in the United States for many decades. Are there any improvements in health care that could reduce these rates further?
Stretching exercises may reduce risk of pre-eclampsia during pregnancy
Stretching exercises may be more effective at reducing the risk of preeclampsia than walking is for pregnant women who have already experienced the condition and who do not follow a workout routine, according to researchers at the University of North Carolina at Chapel Hill School of Nursing.
Mothers' high normal blood sugar levels place infants at risk for birth problems
Pregnant women with blood sugar levels in the higher range of normal-but not high enough to be considered diabetes-are more likely than women with lower blood sugar levels to give birth to babies at risk for many of the same problems seen in babies born to women with diabetes during pregnancy, according to a study funded in large part by the National Institutes of Health.
New finding may help explain development of preeclampsia
In a study of pregnant women, those with pregnancy-induced high blood pressure were found to have higher levels of a peptide that raises blood pressure in the pieces of tissue linking mother and fetus, according to researchers at Wake Forest University Baptist Medical Center.
Stop eating for two: obese moms-to-be should gain less weight than currently recommended
Severely obese women should lose weight during pregnancy, while obese women who are pregnant should gain less weight than currently recommended, a Saint Louis University study finds.
Researchers test old drug with new hopes for pre-eclampsia cure
Researchers at the University of Texas Medical Branch at Galveston are trying to determine whether a drug already available to heart patients can also be used to delay delivery in expectant mothers with severe preeclampsia.
Low vitamin D during pregnancy linked to preeclampsia
Vitamin D deficiency early in pregnancy is associated with a five-fold increased risk of preeclampsia.
Disparities in infant mortality not related to race, study finds
The cause of low birth weights among African-American women has more to do with racism than with race, according to a report by an associate professor of pediatrics at the University of Illinois at Chicago.
Pregnancy Nausea/Vomiting May Indicate Lower Risk of Breast Cancer
It may not seem so at the time, but women who suffer through morning sickness during their pregnancies actually may be fortunate.
New placenta screening for high-risk pregnancies
For the first time ever, a team of Toronto researchers are using a combination of ultrasound and blood tests to screen high-risk pregnant mothers for placental damage.
More Preeclampsia News Articles
| © 2008 BrightSurf.com |