Link between high levels of a protein HtrA1 and preeclampsia

Feb 5 2006

Mayo Clinic researchers have found an association between abnormally high levels of a protein named HtrA1 and preeclampsia, a sudden and dangerous rise in blood pressure that can result in premature delivery, disability or death for mother and fetus.

The condition, which affects 5 to 8 percent of pregnancies worldwide, constitutes a medical emergency and often requires a Caesarean section delivery. The condition is estimated to cause 50,000 to 76,000 maternal deaths each year.

The Mayo Clinic work is the first to link high levels of HtrA1 in third-trimester placental tissues with severe preeclampsia. The results will be reported at the Society for Maternal-Fetal Medicine annual meeting in Miami.

Though preliminary, the findings may one day lead to development of a blood test to track HtrA1 levels to identify women at risk of preeclampsia. Currently no predictive test exists for preeclampsia.

Notes Brian Brost, M.D., Mayo Clinic high-risk pregnancy specialist and senior study investigator, "It is certainly too early to say HtrA1 is a biomarker of preeclampsia, but the initial results are really encouraging, because the cause of this serious complication of pregnancy has not been well understood."

Funminiyi Ajayi, M.D., Mayo researcher and co-author of the paper, collected the placental samples and reviewed the results. "From a basic science point of view, this is an important contribution to understanding a complex series of events that we hope one day to be able to reverse or prevent," says Dr. Ajayi.

Significance of the Mayo Clinic Research

The Mayo Clinic researchers are the first to take two important steps toward developing a better understanding of preeclampsia. These "firsts" consist of:

1. Evaluating an association between preeclampsia and levels of HtrA1 found in placental tissues. The Mayo Clinic researchers tested levels of HtrA1 in specific cells of placentas obtained from women diagnosed with preeclampsia and compared these tissue samples to placentas from normal deliveries. Thirty placentas were evaluated. All placental pairs -- normal and preeclamptic -- were matched by gestational stage. Placentas were categorized in terms of the mother's blood pressure as "normal," "mild preeclampsia" and "severe preeclampsia," according to accepted criteria set by the American College of Obstetricians and Gynecologists. Patients with underlying diseases -- such as diabetes -- that might alter blood pressure were not included in the study.
2. Documenting that the level of HtrA1 is altered in placental tissue from preeclamptic women. In the Mayo Clinic investigation, HtrA1 was found in higher amounts in third-trimester placentas of women with severe preeclampsia. Because greater amounts of HtrA1 indicate greater placental distress and disease severity, developing a blood test to detect levels of HtrA1 may possibly serve as an early warning system that placental conditions are changing. The hope is that such a predictive test would allow physicians to manage preeclampsia on a nonemergency basis when it is less threatening for mother and fetus, or possibly to devise therapies to stop the process or prevent it altogether, according to Dr. Brost.

Background Biology

Prior to the current Mayo Clinic investigation, the protein HtrA1 was known to be involved in programmed cell death, cell change and "invasiveness," the ability of cells to invade and colonize new areas. This process can be healthy -- as in establishing growth of a placenta in the uterus during the first trimester. Invasion also can be unhealthy -- as in the cases of cancer, another context in which the role of HtrA1 has been well studied.

In the Mayo Clinic investigation into HtrA1 and preeclampsia, findings suggest that the increased levels of HtrA1 impair correct functioning during the second stage of growth of key placental cells called cytotrophoblasts. Their job is to invade the uterus to establish the placenta. Just how HtrA1 does this is not known. One possibility is that its molecules "fit" into place in the molecular puzzle to activate abnormal growth. This is theoretically possible because HtrA1 molecules are structurally similar to other molecules, insulin-like growth factors (IGF) binding proteins, according to the Mayo Clinic researchers. Research has shown that an excess IGF binding protein disrupts the growth of cytotrophoblasts and also leads to the dysfunction of the placenta and impaired fetal growth.