Immune mechanisms and circulating mediators may be important in the pathogenesis of preeclampsia. We review our findings on agonistic antibodies against the angiotensin II (Aug II) receptor (AT1-AA) and their possible role in the pathogenesis of this disorder. AT1-AA appear in the course of preeclampsia and are largely gone by 6 weeks after delivery. AT1-AA detection relies on a bioassay using spontaneously beating neonatal rat cardiomyocytes. Their specificity has been documented by other methods, including Western blotting, co-localization, and co-immunoprecipitation experiments. AT1-AA induce signaling in vascular cells and trophoblasts including transcription factor activation. The signaling results in tissue factor production and reactive oxygen species generation, both of which have been implicated in preeclampsia. The role of AT1-AA in preeclampsia and other severe hypertensive conditions has not yet been proved with certainty. However, we believe the findings are compelling and warrant further study.
1. Report of the National High Blood Pressure Education Program Working Group on high Blood Pressure in Pregnancy. Am J Obstet Gynecol2000;183:S1-S22.
2.
2. American College of Obstetricians and Gynecologists. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Int J Gynaecol Obstet2002;77:67-75.
3.
3. Dekker GA. Risk factors for preeclampsia. Clin Obstet Gynecol1999;42:422-435.
4.
4. Benigni A, Gregorini G, Frusca T, et al. Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension. N Engl J Med1989;321:357-362.
5.
5. Roberts JM. Preeclampsia: What we know and what we do not know. Semin Perinatol2000;24:24-28.
6.
6. Borghi C, Esposti DD, Cassani A, Immordino V, Bovicelli L, Ambrosioni E. The treatment of hypertension in pregnancy. J Hypertens2002;20Suppl 2:S52-S56.
7.
7. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: A randomised placebo-controlled trial. Lancet2002;359:1877-1890.
8.
8. Granger JP, Alexander BT, Llinas MT, Bennett WA, Khalil RA. Pathophysiology of preeclampsia: Linking placental ischemia/hypoxia with microvascular dysfunction. Microcirculation2002;9:147-160.
9.
9. Dietl J. The pathogenesis of pre-eclampsia: New aspects. J Perinat Med2000;28:464-471.
10.
10. Roberts JM, Taylor RN, Goldfien A. Endothelial cell activation as a pathogenetic factor in preeclampsia. Semin Perinatol1991;15:86-93.
11.
11. Taylor WR. Mechanical deformation of the arterial wall in hypertension: A mechanism for vascular pathology. Am J Med Sci1998;316:156-161.
12.
12. Roberts JM, Lain KY. Recent Insights into the pathogenesis of pre-eclampsia. Placenta2002;23:359-372.
13.
13. Fisher SJ. The placenta dilemma. Semin Reprod Med2000;18:321-326.
14.
14. Davidge ST, Signorella AP, Lykins DL, Gilmour CH, Roberts JM. Evidence of endothelial activation and endothelial activators in cord blood of infants of preeclamptic women. Am J Obstet Gynecol1996;175:1301-1306.
15.
15. Haller H, Hempel A, Homuth V, et al. Endothelial-cell permability and protein kinase C in pre-eclampsia. Lacet1998;351:945-949.
16.
16. Maynard SE, Min JY, Merchan J, et al. Exces placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest2003;111:649-658.
17.
17. Li C, Ansari R, Yu Z, Shah D. Definitive molecular evidence of renin-angiotensin system in human uterine decidual cells. Hypertension2000;36:159-164.
18.
18. Patrick T, Roberts JM. Current concepts in preeclampsia. MCN Am J Matern Child Nurs1999;24:193-200.
19.
19. Gant NF, Daley GL, Chang S, Whalley PJ, MacDonald PC. A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Inest1973;52:2682-2689.
20.
20. Baker PN, Kilby MD, Pipkin FB. The effect of angiotensin II on platelet intracellular free calcium concentration in human pregnancy. J Hypertens1992;10:55-60.
21.
21. Haller H, Oeney T, Hauck U, Distler A, Philipp T. Increased intracellular free calcium and sensitivity to angiotensin II in platelets of preeclamptic women. Am J Hypertens1989;2:238-243.
22.
22. Hanssens M, Keirse MJ, Spitz B, van Assche FA. Angiotensin II levels in hypertensive and normotensive pregnancies. Br J Obstet Gynaecol1991;98:155-161.
23.
23. Ward K, Hata A, Jeunemaitre X, et al. A molecular variant of angiotensinogen associatedw with preeclampsia. Nat Genet1993;4:59-61.
24.
24. Inoue I, Rohrwasser A, Helin C, et al. A mutation of angiotensinogen in a patient with preeclampsia leads to altered kinetics of the renin-angiotensin system. J Biol Chem1995;270:11430-11436.
25.
25. Morgan T, Craven C, Lalouel JM, Ward K. Angiotensinogen Thr235 variant is associated with abnormal physiologic change of the uterine spiral arteries in first-trimester decidua. Am J Obstet Gynecol1999;180:95-102.
26.
26. Morgan T, Craven C, Nelson L, Lalouel JM, Ward K. Angiotensinogen T235 expression is elevated in decidual spiral arteries. J Clin Invest1997;100:1406-1415.
27.
27. Galao AO, de Souza LH, da Costa BE, Scheibe RM, de Figueiredo CE. Angiotensin-converting enzyme gene polymorphism in preeclampsia and normal pregnancy. Am J Obstet Gynecol2004;191:821-824.
28.
28. Haller H, Ziegler EM, Homuth V, et al. Endothelial adhesion molecules and leukocyte integrins in preeclamptic patients. Hypertension1997;29:291-296.
29.
29. Fu ML, Herlitz H, Schulze W, et al. Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension. J Hypertens2000;18:945-953.
30.
30. Wallukat G, Homuth V, Fischer T, et al. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest1999;103:945-952.
31.
31. Dechend R, Homuth V, Wallukat G, et al. AT(1) receptor agonsitic antibodies from preeclamptic patients cause vascular cells to express tissue factor. Circulation2000;101:2382-2387.
32.
32. Dechend R, Viedt C, Muller DN, et al. AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase. Circulation2003;107:1632-1639.
33.
33. Oian P, Omsjo I, Maltau JM, Osterud B. Increased sensitivity to thromboplastin synthesis in blodo monocytes from pre-eclamptic patients. Br J Obstet Gynaecol1985;92:511-517.
34.
34. Kanfer A, Bruch JF, Nguyen G, et al. Increased placental antifibrinolytic potential and fibrin deposits in pregnancy-induced hypertension and preeclampsia. Lab Invest1996;74:253-258.
35.
35. Schjetlein R, Abdelnoor M, Haugen G, Husby H, Sandset PM, Wisloff F. Hemostatic variables as independent predictors for fetal growth retardation in preeclampsia. Acta Obstet Gynecol Scand1999;78:191-197.
36.
36. Luther T, Flossel C, Mackman N, et al. Tissue factor expression during human and mouse development. Am J Pathol1996;149:101-113.
37.
37. Carmeliet P, Mackman N, Moons L, et al. Role of tissue factor in embryonic blood vessel development. Nature1996;383:73-75.
38.
38. Osterud B. Tissue factor: A complex biological role. Thromb Haemost1997;78:755-758.
39.
39. Nishimura H, Tsuji H, Masuda H, et al. Angiotensin II increases plasminogen activator inhibitor-1 and tissue factor mRNA expression without changing that of tissue type plasminogen activator or tissue factor pathway inhibitor in cultured rat aortic endothelial cells. Thromb Haemost1997;77:1189-1195.
40.
40. Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: Role in cardiovascular biology and disease. Circ Res2000;86:494-501.
41.
41. Taniyama Y, Griendling KK. Reactive oxygen species in the vasculature: Molecular and cellular mechanisms. Hypertension2003;42:1075-1081.
42.
42. Lassegue B, Clempus RE. Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol2003;285:R277-R297.
43.
43. Hanna IR, Taniyama Y, Szocs K, Rocic P, Griendling KK. NAD(P)H oxidase-derived reactive oxygen species as mediators of angiotensin II signaling. Antioxid Redox Signal2002;4:899-914.
44.
44. Griendling KK, Ushio-Fukai M. Reactive oxygen species as mediators of angiotensin II signaling. Regul Pept2000;91:21-27.
45.
45. Xia Y, Wen H, Bobst S, Day MC, Kellems RE. Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells. J Soc Gynecol Investig2003;10:82-93.
46.
46. Caniggia I, Grisaru-Gravnosky S, Kuliszewsky M, Post M, Lye SJ. Inhibition of TGF-beta 2 restores the invasive cpaability of extravillous trophoblasts in preeclamptic pregnancies. J Clin Invest1999;103:1641-1650.
47.
47. Wallukat G, Nissen E, Niechel D, Harris J. Spontaneously beating neonatal rat heart myocyte cultureāA model to characterize angiotensin II at(1) receptor autoantibodies in patients with preeclampsia. In Vitro Cell Dev Biol Anim2002;38:376-377.
48.
48. AbdAlla S, Lother H, el Massiery A, Quitterer U. Increased AT(1) receptor heterodimers in preeclampsia mediate enhanced angiotensin II responsiveness. Nat Med2001;7:1003-1009.
49.
49. Bohlender J, Ganten D, Luft FC. Rats transgenic for human renin and human angiotensinogen as a model for gestational hypertension. J Am Soc Nephrol2000;11:2056-2061.
50.
50. Dzau VJ, Burt DW, Pratt RE. Molecular biology of the reninangiotensin system. Am J Physiol1988;255:F563-F573.
51.
51. de Boer RA, Pinto YM, Suurmeijer AJ, et al. Increased expression of cardiac angiotensin II type 1 (AT(1)) receptors decreases myocardial microvessel density after experimental myocardial infarction. Cardiovasc Res2003;57:434-442.
52.
52. Shimizu T, Okamoto H, Chiba S, et al. VEGF-mediated angiogenesis is impaired by Angiotensin type 1 receptor blockade in cardiomyopathic hamster hearts. Cardiovasc Res2003;58:203-212.
53.
53. Luttun A, Carmeliet P. Soluble VEGF receptor Flt1: The elusive preeclampsia factor discovered?J Clin Invest2003;111:600-602.
54.
54. Page EL, Robitaille GA, Pouyssegur J, Richard DE. Introduction of hypoxia-inducible factor-1alpha by transcriptional and translational mechanisms. J Biol Chem2002;277:48403-48409.
55.
55. Rajakumar A, Doty K, Daftary A, Harger G, Conrad KP. Impaired oxygen-dependent reduction of HIF-1alpha and -2alpha proteins in pre-eclamptic placentae. Placenta2003;24:199-208.
