Multiple soluble TGF-β receptors in addition to soluble endoglin are elevated in preeclamptic serum and they synergistically inhibit TGF-β signaling

Context: Preeclampsia (PE) can be classified into early-onset (<34 weeks of gestation) and late-onset (>34 weeks of gestation) subtypes. Soluble endoglin, an auxiliary receptor for transforming growth factor (TGF)-β ligands, is increased in PE circulation and believed to inhibit TGF-β action by sequestering the ligands. However, soluble endoglin, with a low affinity to TGF-β ligands, has been demonstrated to have little effect by itself on TGF-β action. Objectives: We examined whether multiple soluble TGF-β receptors are elevated in PE circulation and whether they synergistically block TGF-β signaling. Design: TGF-β receptors were measured using enzyme-linked immunosorbent assay in sera collected from preeclamptic pregnancies and gestation-age-matched controls. TGF-β signaling was assessed using an in vitro bioassay and a tube formation assay. Results: TGF-β type I, II, and III receptors were all identified in pregnant serum; all were substantially elevated in early-onset but not late-onset PE. Endoglin was increased in both subtypes. At the greatest concentrations detected in PE, none of these soluble TGF-β receptors alone, including endoglin, inhibited TGF-β signaling. However, when all four soluble receptors were present, signaling of both TGF-β1 and TGF-β2 was substantially reduced. Removal of any one of these soluble receptors alleviated TGF-β1 inhibition; however, removal of soluble TGFbRIII was necessary to relieve TGF-β2 inhibition. Conclusions: Multiple soluble TGF-β receptors are present in pregnant circulation and elevated in early-onset PE; they synergistically inhibit TGF-β signaling, which might be more likely to occur in early-onset than late-onset PE. Reducing soluble TGFbRIII, rather than endoglin, would be more effective in alleviating the inhibition of both TGF-β1 and TGF-β2 signaling in PE.