Response to Questionable Role of the Angiotensin II Receptor Subtype 1 Autoantibody in the Pathogenesis of Preeclampsia: There Is No Single Universal Preeclampsia Cause
We appreciate the interest that Stepan and Walther1 have shown in our studies.2,3 Preeclampsia is an ancient problem, and we do not claim that we have identified the resolution. A number of interesting participants have been introduced recently, including soluble fms-like tyrosine kinase-1 (sFlt1), soluble endoglin, asymmetrical dimethylarginine, and activating autoantibodies to the angiotensin II receptor subtype 1 (AT1-AA). Walther et al4 indeed recently provided additional information on AT1-AA. They concluded from their study that AT1-AA generation appears to be associated with distinct types of pregnancy disorders resulting from impaired placental development and that AT1-AA may be causative. In their letter to the editor, they describe a pregnant patient with hydrops, parvovirus infection (the virus exhibits the same epitopic sequence as the second extracellular loop of AT1-AA), a preeclampsia-like syndrome, sFlt1, and AT1-AA. With therapeutic resolution of the hydrops, sFlt1 decreased by 30% but was still in the “preeclamptic range” (7489 pg/mL), AT1-AA stayed at the initial level, and the hypertension resolved. On the basis of these findings, Stepan and Walther1 conclude that AT1-AA is irrelevant to preeclampsia.
Stepan and Walther1 may be right, but we feel that the jury is still out. After all, sFlt1 in their patient was still in the preeclamptic range despite improvement, and they did not choose to attack that issue. It should also be noted that substantial numbers of women with preeclampsia do not have elevated sFlt1–plasma concentrations.5
The important issue arising from the 2 publications that Stepan and Walter refer to is that AT1-AA has to be judged in context with the surrounding physical and metabolic milieu. As we showed in our publication, AT1-AA may interact with an increased expression of the angiotensin II receptor subtype 1 in the decidua of preeclamptic patients.2 The interaction between the renin-angiotensin system and sFlt-1 was discovered recently by Zhou et al.6 This interaction was also present 1 year after a preeclamptic pregnancy.3 However, we would like to congratulate Stepan et al7 on their recent study separating parvovirus infections from the generation of AT1-AA. Those results would appear to remove at least 1 candidate mechanism from being responsible for the production of AT1-AA. Still, at the moment, there are more questions than answers, except one: there is no single universal preeclampsia cause.
Stepan H, Walther T. Questionable role of the angiotensin II receptor subtype 1 autoantibody in the pathogenesis of preeclampsia. Hypertension. 2007; 50: e3.
Herse F, Dechend R, Harsem NK, Wallukat G, Janke J, Qadri F, Hering L, Muller DN, Luft FC, Staff AC. Dysregulation of the circulating and tissue-based renin-angiotensin system in preeclampsia. Hypertension. 2007; 49: 604–611.
Hubel CA, Wallukat G, Wolf M, Herse F, Rajakumar A, Roberts JM, Markovic N, Thadhani R, Luft FC, Dechend R. Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia. Hypertension. 2007; 49: 612–617.
Walther T, Wallukat G, Jank A, Bartel S, Schultheiss HP, Faber R, Stepan H. Angiotensin II type 1 receptor agonistic antibodies reflect fundamental alterations in the uteroplacental vasculature. Hypertension. 2005; 46: 1275–1279.
Powers RW, Roberts JM, Cooper KM, Gallaher MJ, Frank MP, Harger GF, Ness RB. Maternal serum soluble fms-like tyrosine kinase 1 concentrations are not increased in early pregnancy and decrease more slowly postpartum in women who develop preeclampsia. Am J Obstet Gynecol. 2005; 193: 185–191.
Zhou CC, Ahmad S, Mi T, Xia L, Abbasi S, Hewett PW, Sun C, Ahmed A, Kellems RE, Xia Y. Angiotensin II induces soluble fms-Like tyrosine kinase-1 release via calcineurin signaling pathway in pregnancy. Circ Res. 2007; 100: 88–95.