Soluble Endoglin and Other Circulating Antiangiogenic Factors in Preeclampsia

Abstract

The circulating antiangiogenic protein soluble fms-like tyrosine kinase 1 (sFlt1), also known as soluble vascular endothelial growth factor (VEGF) receptor 1, sequesters the proangiogenic proteins placental growth factor (PlGF) and VEGF. Its circulating level correlates with the severity of preclampsia and with the onset of hypertension or proteinuria. Increased expression of sFlt1 in pregnant rats creates a state resembling preeclampsia. Soluble endoglin, a coreceptor for transforming growth factors, is another antiangiogenic protein that acts with sFlt1 to produce a severe preeclampsia-like syndrome in pregnant rats. This nested case-control study, enrolling healthy nulliparous women taking part in the Calcium for Preeclampsia Prevention (CPEP) trial, was designed to show whether endoglin is associated with preeclampsia in humans. Seventy-two women having preeclampsia before 37 weeks’ gestation were compared with four groups, each comprising 120 women, who had preeclampsia at term; had gestational hypertension; were normotensive but had an small-for-gestational-age infant; or were normotensive and delivered a normal-sized infant. Severe preeclampsia developed in 61% of women with preterm preeclampsia and 25% of those with preeclampsia at term (after 37 weeks’ gestation). Symptomatic women with preterm preeclampsia had significantly higher serum levels of soluble endoglin than control women. Term preeclampsia also was associated with elevated circulating levels of endoglin. At 17–20 weeks’ gestation, endoglin levels were significantly higher in women who later developed preterm preeclampsia than in control women. The same was the case at gestational weeks 25 through 28 for women who developed term preeclampsia. Elevated endoglin levels usually were accompanied by an increased sFlt1:PlGF ratio. The risk of preeclampsia was greatest for women in the highest quartile of the control distributions for both biomarkers but not for either one alone. On multivariable analysis, large increases in the risk of preeclampsia with a small-for-gestational-age infant were associated with the highest quartile of soluble endoglin or sFlt1:PlGF ratio. These findings, combined with those of experimental rodent studies, suggest that circulating soluble endoglin and sFlt1—which cause endothelial dysfunction by different mechanisms—may contribute to the development of preeclampsia. Whether levels of these biomarkers will be useful in predicting the onset of clinical preeclampsia remains to be determined by longitudinal prospective studies.