The basic research effort to implicate soluble endoglin (sEng) and soluble fms-like tyrosine kinase 1 (sFlt-1) in preeclampsia was led by a coauthor of the current paper, S. Ananth Karumanchi, M.D., a nephrologist at the Beth Israel Deaconess Medical Center in Boston.
Dr. Karumanchi began by examining placentas from women who had developed preeclampsia during their pregnancies. He found that these placentas produced high levels of sFlt1, a molecule which exists in two forms. The non-soluble form, Flt1, is found on the inner lining of blood vessels. Both PlGF and another protein, vascular endothelial growth factor (VEGF), bind to Flt. This binding is needed for the normal growth and health of the lining of blood vessels. However, in preeclampsia, the soluble form, sFlt1, circulates through the bloodstream, soaking up PlGF and VEGF, preventing them from sustaining the blood vessels.
In a study published in the March 2003 issue of The Journal of Clinical Investigation and funded in part by NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Karumanchi and his coworkers found that blood vessel cells incubated with the blood serum from women with preeclampsia appeared frayed and less healthy than blood vessel cells grown with the serum from women with normal pregnancies. Finally, pregnant rats injected with a virus that caused them to produce excess amounts of sFlt1 developed high blood pressure and protein in the urine, similar to that seen in women with preeclampsia. Moreover, Karumanchi found high levels of sFlt1 in the blood of 21 women with preeclampsia.
To test the theory, Dr. Richard Levine of the National Institutes of Health, Dr. Karumanchi and their coworkers began a collaborative effort. From 1992 to 1995, Dr. Levine had conducted a study to determine if providing calcium supplements to pregnant women could prevent the development of preeclampsia. The calcium treatment proved ineffective, but the study yielded blood and urine samples from more than 4500 pregnant women at three intervals during their pregnancies.
In 2004, the researchers published the results of their first analysis in the New England Journal of Medicine, showing that a group of 120 women with preeclampsia, when compared to a control group, had 3 times the blood level of sFlt1 and reduced levels of both VEGF and PlGF, after they developed preeclampsia. Moreover, they showed that abnormalities in the levels of these molecules began more than a month before clinical signs of preeclampsia. (That study is described at http://www.nichd.nih.gov/news/releases/Pages/preeclampsia.aspx.
In a second analysis of the sample, the researchers found that urinary levels of PlGF began decreasing by the 25th week of pregnancy in women who later developed preeclampsia. In that study, the researchers concluded that detecting urinary levels of PlGF might provide the basis for a test in a biological fluid which is more easily obtained than a blood sample, to predict which women would develop the condition. (A release describing that study is available at http://www.nichd.nih.gov/news/releases/Pages/sub_preeclampsia.aspx.)
Although the results of those initial studies were promising, the findings failed to account for all cases of preeclampsia. Some of the women with high sFlt1 levels did not develop preeclampsia; conversely, some women with low sFlt1 levels did develop the condition.
Dr. Karumanchi reviewed the findings from his original analysis of placentas and found that women with preeclampsia had high levels of a second substance in their bloodstream: Endoglin. Like sFlt1, endoglin existed in a soluble form, which circulated in the bloodstream, and a form that was fixed to the lining of blood vessels. Similar to the way in which VEGF and PlGF bind to Flt1, a molecule known as transforming growth factor (TGF beta) binds to endoglin, in the process keeping blood vessels healthy.
But the soluble form of endoglin appears to tie up available TGF beta. Deprived of TGF beta, the blood vessels become less elastic. This results in greater tension in the blood vessels, causing blood pressure to rise. In a study funded by the NIDDK and the National Heart, Lung, and Blood Institute and published in Nature Medicine, Dr. Karumanchi and his collaborator, Dr. Michelle Letarte, from the Hospital for Sick Children at Toronto, reported that the most severe form of preeclampsia developed in pregnant rats treated with viruses that caused the animals to produce excessive amounts of soluble endoglin and sFlt1.
That finding led to the publication of the current study, published in the September 7 New England Journal of Medicine. Drs. Levine and Karumanchi searched samples remaining from the earlier calcium and preeclampsia study and determined that altered levels of both soluble endoglin and sFlt1 contribute to the development of preeclampsia in pregnant women.
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