Published online before print February 7, 2008, doi: 10.1161/HYPERTENSIONAHA.107.100735
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(Hypertension. 2008;51:991.)
© 2008 American Heart Association, Inc.
Go Red Editorial Commentaries |
Preeclampsia Pathogenesis
"Triple A Rating"–Autoantibodies and AntiAngiogenic Factors
From the Beth Israel Deaconess Medical Center and Harvard Medical School (S.A.K.), Boston, Mass; and the University of Chicago (M.D.L.), Ill.
Correspondence to S. Ananth Karumanchi, Beth Israel Deaconess Medical Center, 330 Brookline Ave, RW 663, Boston, MA 02215. E-mail sananth{at}bidmc.harvard.edu
Preeclampsia, a major killer of mother and fetuses, has traditionally been called the disease of theories, but research these past decades is changing all of that. Early observations related to this disorder were that all of the signs and symptoms typically resolve rapidly after the delivery of the placenta. Thus, it was natural to focus on this organ as the source of the disease. In this respect, 2 antiangiogenic proteins, overproduced in the placenta, that gain access to the maternal circulation have become candidate molecules responsible for phenotypic preeclampsia. One is soluble Fms-like tyrosine kinase-1 (sFlt1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor signaling that may regulate placental angiogenesis, and the other is soluble endoglin, a circulating coreceptor that may inhibit transforming growth factor-β1 signaling in the vasculature.1 Maternal blood levels of both of these antiangiogenic proteins are increased in preeclamptic patients compared with those in uncomplicated pregnancies weeks to months before overt signs and symptoms.1 Adenoviral overexpression of sFlt1 and soluble endoglin in rodents produces preeclampsia-like phenotypes, including severe hypertension, proteinuria, glomerular endotheliosis, and features resembling the HELLP syndrome (hemolysis, elevated liver enzymes, low platelet syndrome) in humans.2 The increased risk of preeclampsia in women with multifetal pregnancies, trisomy 13, primiparity, high altitudes, and mirror syndrome may also be explained by alterations in circulating antiangiogenic factors (reviewed in Reference 3).
However, as data supporting a significant role for antiangiogenic factors in producing the maternal syndrome is gradually unfolding (research focused primarily on sFlt1), the cause of the impaired placentation and the upregulation of antiangiogenic proteins in placentas of women destined to develop preeclampsia remains unknown. Various investigators have hypothesized that oxidative stress, syncytial debris, altered NK cell signaling, hypoxia, and altered hemeoxygenase expression may be responsible for the excess sFlt1 noted in preeclampsia4–6; however, it is safe to say that the cause of this aberration is still unknown. The contribution of Zhou et al7 resurrects a candidate area discarded decades ago, the renin-angiotensin system.
An the early observations relating to pressor hormones in preeclamptic women was the enhanced expression of several components of the renin-angiotensin system in preeclampsia that were greater than those in normotensive-pregnant populations and markedly greater than in nonpregnant populations. This excitement dissipated rapidly with the discovery that plasma-renin activity, circulating angiotensin II levels, and aldosterone excretion in preeclamptic patients were lower than those measured in normotensive pregnant women.8 However, the discovery of the tissue-based renin-angiotensin system in the uteroplacental unit and clinical studies suggesting that preeclamptic women are more sensitive to the pressor effects of angiotensin II, the latter occurring before overt disease, remained a source of investigator interest in the role of renin-angiotensin system in preeclampsia for decades.8 In 1999, in a signal article, a research team headed by Fred Luft in Berlin noted that autoantibodies agonistic to the angiotensin II type 1 (AT1) receptor were present in the circulation of preeclamptic women.9 These observations, however, were not specific for preeclampsia, producing skepticism among critics. However, subsequent work that demonstrated the presence of autoantibodies in a transgenic model of preeclampsia by the same group,10 as well as data from Xia and Kellems’ group in Houston, the latter investigators linking the autoantibodies to oxidative stress and shallow placentation (a characteristic of the preeclampsia) have focused our interest on this hypothesis again.11,12
The article by Zhou et al7 in this issue of Hypertension is particularly exciting because it marries autoantibodies to antiangiogenic factors (the triple A rating upgrade) by suggesting that these circulating autoantibodies may be responsible for placental sFlt1 upregulation in preeclampsia, observations extending a previous finding from the same group that angiotensin II stimulates sFlt1 production in placental explants.13 The authors used various approaches, perhaps the most elegant being the following: IgG from preeclamptic patients increased production of sFlt1 in placental villous cultures that were blocked by an AT1 receptor blocker. Furthermore, using gene silencing, they demonstrated that AT1 signaling induces sFlt1 mRNA and protein and ant-angiogenic activity in endothelial cells and trophoblasts. Perhaps the "coups de resistance" was the demonstration that introduction of IgG from preeclamptic patients induced increased sFlt1 in pregnant mice but not in nonpregnant mice, suggesting that the antibodies required the placenta for the sFlt1 upregulation. These data suggest a link whereby the AT1 autoantibodies may be the cause of increased sFlt1 levels during pregnancy in women destined to have preeclampsia, a mechanism mediated via the placenta.
Having extolled these findings, we must note some inconsistencies that must be resolved before ascribing AT1 autoantibodies a pathogenic role in preeclampsia. Already mentioned is the fact that these antibodies are not peculiar to preeclampsia, having been detected in patients with accelerated hypertension and vascular rejection,14,15 but these latter disorders occur in the absence of a placenta. Other concerns are the following: aldosterone production, which is downstream to angiotensin II signaling, is suppressed (not elevated) in preeclampsia. Whether the suppression of aldosterone is because of a second abnormality in preeclampsia, such as defective aldosterone synthase activity, remains unknown.16 An answer is required to the old question regarding immune mechanisms in preeclampsia of why the incidence is greatest in the first pregnancy instead of becoming increasingly worse with subsequent conceptions (if preeclampsia is an autoimmune disease). Furthermore, immunosuppressive medications, such as steroids and/or plasmapheresis, that are typically effective in antibody-mediated disorders have not made significant improvement in the treatment of preeclampsia. Still another question is why are fetuses, who manifest antibody levels similar to the mother’s, protected from the signs and symptoms of preeclampsia?17 AT1 antibodies are also present in normotensive gravidas with intrauterine growth restriction but no signs or symptoms of preeclampsia.18
Finally, we note the need for further studies here. It would be of interest to see whether AT1 autoantibodies were responsible for soluble endoglin upregulation as well and whether rodents injected with AT1 antibodies manifest preeclampsia phenotypes of hypertension, proteinuria, and glomerular endotheliosis. Clinical data demonstrating that changes in AT1 autoantibodies antedate changes in circulating sFlt1 in patients destined to develop preeclampsia would further strengthen the hypothesis that the generation of the AT1 autoantibody may the primary abnormality in preeclampsia. It would also be important to clarify whether the maternal or the placental (fetal) AT1 receptors contribute to the antigen load and autoimmunity. In spite of all of these unanswered questions, the finding by Zhou et al7 that AT1 autoantibodies may upregulate sFlt1 raises hope that antagonism of the AT1 signaling pathway in preeclamptic patients may be a useful therapeutic target in these patients.
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Acknowledgments |
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Sources of Funding
S.A.K. is funded by National Institutes of Health RO1 grants (DK065997 and HL079594).
Disclosures
S.A.K. is a coinventor of multiple patents held by the Beth Israel Deaconess Medical Center for the diagnosis and therapy of preeclampsia. S.A.K. is a consultant to Johnson & Johnson, Beckman Coulter, and Abbott Diagnostics. M.D.L. reports no conflicts.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
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2. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D’Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006; 12: 642–649.[CrossRef][Medline] [Order article via Infotrieve]
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