Angiotensin Receptor Agonistic Autoantibody–Mediated Tumor Necrosis Factor-α Induction Contributes to Increased Soluble Endoglin Production in Preeclampsia

Background— Preeclampsia is a prevalent life-threatening hypertensive disorder of pregnancy. The circulating antiangiogenic factor, soluble endoglin (sEng), is elevated in the blood circulation of women with preeclampsia and contributes to disease pathology; however, the underlying mechanisms responsible for its induction in preeclampsia are unknown. Methods and Results— Here, we discovered that a circulating autoantibody, the angiotensin receptor agonistic autoantibody (AT1-AA), stimulates sEng production via AT1 angiotensin receptor activation in pregnant mice but not in nonpregnant mice. We subsequently demonstrated that the placenta is a major source contributing to sEng induction in vivo and that AT1-AA–injected pregnant mice display impaired placental angiogenesis. Using drug screening, we identified tumor necrosis factor-α as a circulating factor increased in the serum of autoantibody-injected pregnant mice contributing to AT1-AA–mediated sEng induction in human umbilical vascular endothelial cells...