Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.
BACKGROUND
Alterations in circulating soluble fms-like tyrosine kinase 1 (sFlt1), an antiangiogenic protein, and placental growth factor (PlGF), a proangiogenic protein, appear to be involved in the pathogenesis of preeclampsia. Since soluble endoglin, another antiangiogenic protein, acts together with sFlt1 to induce a severe preeclampsia-like syndrome in pregnant rats, we examined whether it is associated with preeclampsia in women.


METHODS
We performed a nested case-control study of healthy nulliparous women within the Calcium for Preeclampsia Prevention trial. The study included all 72 women who had preterm preeclampsia (<37 weeks), as well as 480 randomly selected women--120 women with preeclampsia at term (at > or =37 weeks), 120 women with gestational hypertension, 120 normotensive women who delivered infants who were small for gestational age, and 120 normotensive controls who delivered infants who were not small for gestational age.


RESULTS
Circulating soluble endoglin levels increased markedly beginning 2 to 3 months before the onset of preeclampsia. After the onset of clinical disease, the mean serum level in women with preterm preeclampsia was 46.4 ng per milliliter, as compared with 9.8 ng per milliliter in controls (P<0.001). The mean serum level in women with preeclampsia at term was 31.0 ng per milliliter, as compared with 13.3 ng per milliliter in controls (P<0.001). Beginning at 17 weeks through 20 weeks of gestation, soluble endoglin levels were significantly higher in women in whom preterm preeclampsia later developed than in controls (10.2 ng per milliliter vs. 5.8 ng per milliliter, P<0.001), and at 25 through 28 weeks of gestation, the levels were significantly higher in women in whom term preeclampsia developed than in controls (8.5 ng per milliliter vs. 5.9 ng per milliliter, P<0.001). An increased level of soluble endoglin was usually accompanied by an increased ratio of sFlt1:PlGF. The risk of preeclampsia was greatest among women in the highest quartile of the control distributions for both biomarkers but not for either biomarker alone.


CONCLUSIONS
Rising circulating levels of soluble endoglin and ratios of sFlt1:PlGF herald the onset of preeclampsia.
Levine
Richard J
RJ
Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human Development, Department of Health and Human Services, Bethesda, MD 20892, USA. levinerj@mail.nih.gov
Lam
Chun
C
Qian
Cong
C
Yu
Kai F
KF
Maynard
Sharon E
SE
Sachs
Benjamin P
BP
Sibai
Baha M
BM
Epstein
Franklin H
FH
Romero
Roberto
R
Thadhani
Ravi
R
Karumanchi
S Ananth
SA
D015703:Antigens, CD / Q000097:blood*; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D000071063:Endoglin; D005260:Female; D005865:Gestational Age; D006801:Humans; D046110:Hypertension, Pregnancy-Induced / Q000097:blood; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D015999:Multivariate Analysis; D016017:Odds Ratio; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000097:blood* / Q000145:classification; D011247:Pregnancy / Q000097:blood; D011256:Pregnancy Outcome; D011257:Pregnancy Proteins / Q000097:blood*; D016032:Randomized Controlled Trials as Topic; D011956:Receptors, Cell Surface / Q000097:blood*; D012016:Reference Values; D012307:Risk Factors; D012720:Severity of Illness Index; D012907:Smoking / Q000097:blood; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000097:blood*
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C000608036:PGF protein, human; C000608038:Pgf protein, rat; D011257:Pregnancy Proteins; D011956:Receptors, Cell Surface; D000072483:Placenta Growth Factor; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1