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

• Published in: Circulation (New York, N.Y.) N.Y.), 2010-01, Vol.121 (3), p.436-444
• Main Authors: ZHOU, Cissy Chenyi, IRANI, Roxanna A, YANG XIA, YUJIN ZHANG, BLACKWELL, Sean C, TIEJUAN MI, JIAMING WEN, SHELAT, Harnath, GENG, Yong-Jian, RAMIN, Susan M, KELLEMS, Rodney E
• Format: Article
• Language: English
• Subjects: Animals; Autoantibodies - blood; Autoantibodies - pharmacology; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Chorionic Villi - blood supply; Chorionic Villi - immunology; Chorionic Villi - metabolism; Coronary heart disease; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endoglin; Endothelial Cells - metabolism; Female; Heart; Heme Oxygenase-1 - metabolism; Humans; Immunoglobulin G - blood; Immunoglobulin G - pharmacology; Intracellular Signaling Peptides and Proteins - blood; Medical sciences; Mice; Neovascularization, Pathologic - blood; Neovascularization, Pathologic - immunology; Placenta - blood supply; Placenta - immunology; Placenta - metabolism; Pre-Eclampsia - blood; Pre-Eclampsia - immunology; Pregnancy; Receptor, Angiotensin, Type 1 - immunology; Receptor, Angiotensin, Type 1 - metabolism; Signal Transduction - physiology; Solubility; Tumor Necrosis Factor-alpha - blood
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.109.902890

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. Here, we discovered that a circulating autoantibody, the angiotensin receptor agonistic autoantibody (AT(1)-AA), stimulates sEng production via AT(1) 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 AT(1)-AA-injected pregnant mice display impaired placental angiogenesis. Using drug screening, we identified tumor necrosis factor-alpha as a circulating factor increased in the serum of autoantibody-injected pregnant mice contributing to AT(1)-AA-mediated sEng induction in human umbilical vascular endothelial cells. Subsequently, among all the drugs screened, we found that hemin, an inducer of heme oxygenase, functions as a break to control AT(1)-AA-mediated sEng induction by suppressing tumor necrosis factor-alpha signaling in human umbilical vascular endothelial cells. Finally, we demonstrated that the AT(1)-AA-mediated decreased angiogenesis seen in human placenta villous explants was attenuated by tumor necrosis factor-alpha-neutralizing antibodies, soluble tumor necrosis factor-alpha receptors, and hemin by abolishing both sEng and soluble fms-like tyrosine kinase-1 induction. Our findings demonstrate that AT(1)-AA-mediated tumor necrosis factor-alpha induction, by overcoming its negative regulator, heme oxygenase-1, is a key underlying mechanism responsible for impaired placental angiogenesis by inducing both sEng and soluble fms-like tyrosine kinase-1 secretion from human villous explants. Our results provide important new targets for diagnosis and therapeutic intervention in the management of preeclampsia.