This Article Abstract Full Text (PDF) All Versions of this Article: 46/6/1275    most recent 01.HYP.0000190040.66563.04v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Walther, T. Articles by Stepan, H. Search for Related Content PubMed PubMed Citation Articles by Walther, T. Articles by Stepan, H. Pubmed/NCBI databases Medline Plus Health Information High Risk Pregnancy

(Hypertension. 2005;46:1275.)
© 2005 American Heart Association, Inc.

Original Articles

Angiotensin II Type 1 Receptor Agonistic Antibodies Reflect Fundamental Alterations in the Uteroplacental Vasculature

Thomas Walther; Gerd Wallukat; Alexander Jank; Sabine Bartel; Heinz-Peter Schultheiss; Renaldo Faber; Holger Stepan

From the Department of Cardiology and Pneumology, Charité -Campus Benjamin Franklin, Berlin, Germany (T.W., A.J., H.-P.S.); Department of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands (T.W.); Max-Delbrück Center for Molecular Medicine, Hindenburgdamm 30, 12200 Berlin, Germany (G.W., S.B.); and Department of Obstetrics and Gynecology, University of Leipzig, Germany (R.F., H.S.).

Reprint requests to Thomas Walther, Department of Cardiology and Pneumology, Charité -Campus Benjamin Franklin, Berlin, Germany. E-mail thomas.walther{at}charite.de

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Abnormal uterine perfusion detected by Doppler sonography reflects impaired trophoblast invasion, a factor involved in the pathogenesis of pregnancy complications such as preeclampsia or intrauterine growth retardation. Recent studies have demonstrated an autoantibody against the angiotensin type 1 (AT₁) receptor in pregnant women with preeclampsia. Our aim was to determine whether the AT₁ autoantibody precedes the clinical symptoms and is thus predictive of preeclampsia. We therefore detected this antibody in serum from second trimester pregnancies with abnormal uterine perfusion because these women show an indirect sign of inadequate trophoblast invasion. Then the AT₁ autoantibody distribution/concentration was compared with that of women at term with or without pregnancy pathology. The AT₁ autoantibody was already detectable in second trimester pregnant women with abnormal uterine perfusion before the clinical manifestation of preeclampsia (80%). However, it was also found in second trimester pregnant women with abnormal uterine perfusion who later developed intrauterine growth retardation (60%) or even had a normal course of pregnancy (62%). In the third trimester, the AT₁ autoantibody was demonstrated in 89% of patients with manifest preeclampsia, 86% of those with manifest intrauterine growth retardation, and even in healthy pregnant women at term with a history of abnormal uterine perfusion in the second trimester. We conclude that the AT₁ autoantibody is an early but nonspecific marker for preeclampsia. The generation of this antibody seems to be associated with distinct types of pregnancy disorders resulting from impaired placental development. The AT₁ autoantibody may thus be causative for pathological uteroplacental perfusion.

Key Words: angiotensin II • antibodies • hypertension, gestational • preeclampsia • pregnancy • receptors, angiotensin

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
Preeclampsia, a serious pregnancy-specific disorder characterized by proteinuria and hypertension after the 20th week of gestation, is still a leading cause of maternal and neonatal morbidity and mortality. The lack of preventive and causal treatment is mainly attributable to the fact that the etiology and pathophysiology are not understood.¹ Impairment of placental development and trophoblast invasion is thought to be causally associated with preeclampsia. Doppler ultrasound determination of uterine perfusion is a noninvasive tool for measuring uteroplacental vascular resistance and assessing the quality of the trophoblast invasion.² The trophoblast failed to develop adequately in pregnancies with abnormal uterine perfusion. Trophoblast invasion into the maternal compartment is thus impaired, and the pregnant uterus is not transformed into a low-resistance bed. Precisely this pathology is thought to be a pathogenetic feature of pregnancy complications such as preeclampsia or intrauterine growth retardation (IUGR). Abnormal uterine perfusion characterizes pregnancies at risk for these complications and precedes their clinical manifestation. However, only some pregnant women with abnormal uterine perfusion develop a complication, and about two thirds have a normal course of pregnancy despite the high uteroplacental resistance.³

In vitro studies showed that stimulation of the angiotensin type 1 (AT₁) receptor causes reduced trophoblast invasiveness via plasminogen activator inhibitor-1 activation. This effect could also be mediated via an agonistic autoantibody against the angiotensin AT₁ receptor (AT₁-AA).⁴ This autoimmune antibody was recently identified by Wallukat et al as being detectable in preeclamptic patients but not in healthy pregnancies or those with essential hypertension.⁵ A possible causality of the AT₁-AA in preeclampsia has been postulated because AT₁ receptor stimulation by this AT₁-agonistic AT₁-AA in vitro leads to reduced trophoblast invasiveness, a typical characteristic of preeclampsia. Moreover, the antibody induces Ca²⁺ release in vascular smooth muscle cells and could therefore mediate the vascular alterations in preeclampsia.⁶ The hypothesis was further supported by Dechend et al, who demonstrated increased activation of NADPH oxidase. This could contribute to oxidative stress and an inflammatory response, which are pathophysiological factors in preeclampsia.⁷ Thus, the AT₁-AA is discussed as the "missing link" between the still unknown origin of the disease and the variety of maternal symptoms associated with clinically manifest preeclampsia, including hypertension, endothelial dysfunction, and renal damage. The fact that the AT₁-AA is an interesting candidate for mediating or even causing the disease was further supported by the finding that a transgenic rat model of preeclampsia is also characterized by the presence of the AT₁-AA.⁸ However, decisive evidence that the detected autoantibody is causative for preeclampsia has not yet been provided.

Attention was focused on determining whether AT₁-AA precedes the clinical symptoms of preeclampsia or is only a secondary effect of clinically evident preeclampsia and therefore not the primary cause of the disease. To examine this question, we detected the AT₁-AA in serum from second trimester pregnancies with abnormal uterine perfusion as an indirect sign of inadequate trophoblast invasion because these women are likely to develop preeclampsia but have no symptoms of the disease in this phase of the pathophysiological cascade.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
All patients gave written informed consent, and the study was approved by the institutional ethics committee and adhered to the principles of the Declaration of Helsinki. We collected blood from 31 pregnancies with pathological uterine perfusion (18th to 22nd week of gestation) and 21 with normal perfusion. Thirty-six pregnancies in the third trimester with a normal outcome or manifest pathology such as preeclampsia or IUGR were additionally recruited. From the second trimester group with pathological uterine perfusion, 7 patients could be followed longitudinally until delivery and contributed to the third trimester group, with 5 patients with normal outcome, 1 with IUGR, and 1 with preeclampsia.

Preeclampsia was defined according to the guidelines of the International Society for the Study of Hypertension in Pregnancy.⁹ Gestational hypertension is defined here as 1 diastolic blood pressure reading of 110 mm Hg on any occasion or 2 consecutive diastolic blood pressure readings of 90 mm Hg 4 hours apart. Significant proteinuria is defined as 300 mg of total protein in a 24-hour urine collection or, if these data are not available, 1+ proteinuria by dipstick on 2 consecutive occasions 4 hours apart. IUGR was defined as a birth weight below the fifth percentile of our reference group.

The Doppler investigations were performed using a LOGIQ 9 ultrasound device (GE) with a 5.0-MHz convex transducer. Color Doppler imaging was used to identify the uterine artery at the point where it crossed the external iliac artery. The pulsatility index (PI) and the presence or absence of a notch were noted. Uterine perfusion was defined as pathological if there was bilateral notching or if the mean PI of both arteries was greater than the 90th percentile (mean PI>1.45) of our reference group. All pregnancies were singleton, and the women were healthy and normotensive at the time of examination. The persistence of pathological uterine perfusion was confirmed in the 24th week of gestation. After the first Doppler examination, 1 venous blood sample (10 mL) was drawn from each woman into tubes containing EDTA. Immediately after sampling, plasma was separated by centrifugation at 4000g for 10 minutes and frozen at –80°C. The AT₁-AA was measured by the same reference laboratory as described previously,⁵ where mainly the beating rates of focal contractile neonatal rat cardiomyocytes were counted before and after treatment with the purified IgG fraction. The protocol has been modified as follows. The basal contraction rate of spontaneously beating cardiomyocytes was determined. The immunoglobulin fractions from patients were added at a concentration of 1:40, and the beating rate was recounted after 60 minutes. To prove that the positive chronotropic response was AT₁ antibody specific, irbesartan was added at a concentration of 10^–6 M, and the contraction rate was recounted after 5 minutes.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
All women with normal uterine perfusion had a normal course of pregnancy with a normal delivery at term and no symptoms of hypertension or IUGR (Table). None of these women harbored an AT₁-AA at the 20th week of pregnancy, whereas 4 of 5 pregnancies with subsequent development of preeclampsia already tested positive at this time point. However, 3 of 5 women who later developed IUGR but showed no sign of a hypertensive disorder also had the agonistic AT₁ antibody. More interestingly, test results were positive even in 13 of the 21 women with an uneventful pregnancy and normal delivery despite the pathological uterine perfusion (Figure, A). To exclude a gestational age–dependent autoimmune antibody regulation, we performed a second study for AT₁-AA detection in 10 pregnancies with a normal and 26 with an adverse outcome at delivery, also including patients from the first group. Eighty-nine percent of all preeclamptic pregnancies were AT₁-AA positive. As already suggested by positive tests at the 20th week in women who later developed IUGR, the antibody was detectable in 6 of 7 tested pregnancies with IUGR at delivery (Figure, B). Even more important was the fact that 5 of the 10 women without pathology harbored the antibody. A longitudinal investigation of these 5 women disclosed abnormal uterine perfusion at the 20th week of gestation. Finally, by comparing the increase in beat frequency between the groups, we investigated an AT₁-AA concentration-dependent effect on the pathophysiological outcome because only the highest concentrations may complicate a pregnancy by preeclampsia. Noteworthy is the absence of significant differences between the AT₁-AA–positive groups, which excludes a clinically relevant threshold (Figure, C).

View this table: [in this window] [in a new window]   Clinical Data of the Patient Groups

View larger version (37K): [in this window] [in a new window]   Percentage and concentration of the AT1-AA in pregnancies at the early second trimester and at term. Distribution and subdivision of pregnancies at the early second trimester (18th to 22nd week of gestation (51 women; A) and of a reference group at term (36 women) in the presence of an AT1-AA (B). Numbers: negative for AT1-AA/positive for AT1-AA; in parenthesis: percentage of positive tested women within the group. C, Contractility increase in beats per 15 s (mean±SEM) reflecting the AT1-AA concentrations in the autoantibody-positive pregnancies of the different groups. P indicates perfusion; PE, preeclampsia.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The syndrome of preeclampsia has been ascribed previously to generalized maternal endothelial dysfunction, poor placentation, and excessive maternal inflammatory response. Several reports have indicated that increased levels of antiphospholipid antibodies,¹⁰ anti-DNA antibodies,¹¹ or autoantibodies against G-protein–coupled receptors as the AT₁ receptor may be associated with preeclampsia. Our investigations aimed at answering the question of whether the AT₁-AA described as specific for preeclamptic patients is already detectable before the onset of the disease. They were designed to clarify whether the AT₁-AA antedates the clinical manifestation of the disease and could therefore have pathogenetic relevance or is only a phenomenon secondary to preeclampsia. Although our study is the first to show that the AT₁-AA is already detectable in second trimester women with abnormal uterine perfusion and subsequent clinical manifestation of preeclampsia, the antibody was also found in women who later developed other pregnancy diseases such as IUGR and even in those with abnormal uterine perfusion but without later clinical pathology.

Interestingly, all women who tested positive shared the 1 common feature of abnormal uterine perfusion, whereas none of those with normal uterine perfusion harbored the antibody. Testing 15 women at both time points showed that the antibody remained detectable with advancing gestational age, and even the concentrations remained stable. This also excludes alteration of the antibody concentration as a possible tool for predicting whether a woman with abnormal uterine perfusion will develop preeclampsia or IUGR or will have a normal outcome. Thus, the recent postulate that AT₁-AA is specific and possibly causative for preeclampsia has to be revised. This is strongly supported by the observation that a bioactive AT₁-AA with pathological properties is also detectable in nonpregnant patients with renal allograft rejection.¹²

Moreover, the presence of the AT₁-AA correlates with abnormal uterine perfusion regardless of the later course and outcome of the pregnancy. This seems all the more important because abnormal uterine perfusion is caused by elevated uteroplacental impedance attributable to impaired placental development and maturation. Precisely this phenomenon with probable impairment of trophoblast invasion into the maternal compartment causing persistence of a high-pressure system is thought to be the key event in the etiology and pathogenesis of proteinuric hypertensive disorders in pregnancy and IUGR.¹³ Therefore, early occurrence of the AT₁-AA in pregnancy suggests a crucial role of AT₁-AA in all types of placental vascularization disorders. Because there are first attempts to detect an abnormal uterine perfusion in the first trimester as an early screening for preeclampsia,¹⁴ it would be interesting to investigate in upcoming studies, whether the AT₁-AA is detectable even in the first trimester of gestation, because the critical phase of trophoblast invasion and development takes place in this stage.

Because an AT₁ receptor–mediated pathway has also been discussed in kidney-transplanted patients with refractory vascular rejection,¹² this autoantibody may even be a key factor in the development of different types of vasculopathy. However, it still remains to be clarified what triggers the generation of the AT₁-AA early in pregnancy or in nonpregnancy-related vasculopathies and to what antigen the antibody is originally directed.

Because our data confirm that late complications occur in only some pregnancies with abnormal uterine perfusion, additional factors must be involved in the development of preeclampsia or IUGR. Although we identified AT₁-AA–positive patients with abnormal uterine perfusion but a normal outcome, the agonistic antibody clearly interacts with the AT₁ receptor to cause in vitro effects characteristic of preeclampsia such as increased reactive oxygen species generation⁷ and angiotensin II responsiveness.¹⁵ Thus, the antibody in combination with 1 other factors could still be a relevant pathogenetic factor for pregnancy pathology, as also indicated by recent findings of Dechend et al in transgenic rats.⁸

Our study has 2 major implications. The clinical importance of the AT₁-AA has changed in the light of evidence characterizing it as an early but not entirely specific marker for preeclampsia. Interestingly, the AT₁-AA seems to be associated with distinct types of pregnancy disorders that result from impaired placental development, and the process that leads to impaired development of the uteroplacental vasculature is linked to a hitherto unknown antigen presentation or trigger for AT₁-AA generation. Therefore, additional studies are needed to identify the antigen or the AT₁ receptor modification initiating a direct autoimmune response against the receptor. Additional aims are to discover the key event that triggers a disorder in pregnancies with abnormal uterine perfusion and to find out what determines the type of disease that will develop in a particular case.

Perspectives
It is well recognized that autoantibodies such as the AT₁-AA receptor or an anti–ß1-adrenoceptor autoantibody are involved in the pathogenesis of a variety of cardiovascular complications. This had led to first therapeutic implications such as specific or nonspecific removal of these autoantibodies from circulation. Clinical trials are needed to prove whether methods such as therapeutic immunoadsorption are applicable in pregnancy. This would of course not be a causal treatment of hypertensive pregnancy disorders. However, if this therapy could achieve a prolongation of pregnancy, perinatal and maternal morbidity may be already significantly improved.

It would be of great interest to study the presence of detectable levels of AT₁-AA, in combination with impaired perfusion, at the first trimenon. The determined time course of AT₁-AA generation could identify the antibody as a cause or consequence of abnormal perfusion.

Finally, it is still unclear which cofactors are decisive in determining the clinical course of pregnancies with abnormal uterine perfusion in presence of the AT₁-AA. Thus, to clarify the pathophysiological sequence of disturbed placental development, the identification of these cofactors and their interaction with AT₁-AA is the objective of further studies.

	Footnotes

 
The first 2 authors contributed equally to this work.

Received August 25, 2005; first decision September 22, 2005; accepted September 30, 2005.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol. 1999; 179: 1359–1375.
2. Chien PF, Arnott N, Gordon A, Owen P, Khan KS. How useful is uterine artery Doppler flow velocimetry in the prediction of pre-eclampsia, intrauterine growth retardation and perinatal death? An overview. Brit J Obstet Gynaecol. 2000; 107: 196–208.
3. Stepan H, Heihoff-Klose A, Faber R. Reduced antioxidant capacity in second-trimester pregnancies with pathological uterine perfusion. Ultrasound Obstet Gynecol. 2004; 23: 579–583.[Medline] [Order article via Infotrieve]
4. Xia Y, Wen H, Bobst S, Day M-C, Kellems RE. Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells. J Soc Gynecol Investig. 2003; 10: 82–93.[CrossRef][Medline] [Order article via Infotrieve]
5. Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B, Jupner A, Baur E, Nissen E, Vetter K, Neichel D, Dudenhausen JW, Haller H, Luft FC. Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest. 1999; 103: 945–952.[Medline] [Order article via Infotrieve]
6. Thway TM, Shlykov SG, Day MC, Sanborn BM, Gilstrap LC III, Xia Y, Kellems RE. Antibodies from preeclamptic patients stimulate increased intracellular Ca2+ mobilization through angiotensin receptor activation. Circulation. 2004; 110: 1612–1619.[Abstract/Free Full Text]
7. Dechend R, Viedt C, Muller DN, Ugele B, Brandes RP, Wallukat G, Park JK, Janke J, Barta P, Theuer J, Fiebeler A, Homuth V, Dietz R, Haller H, Kreuzer J, Luft FC. AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase. Circulation. 2003; 107: 1632–1639.[Abstract/Free Full Text]
8. Dechend R, Gratze P, Wallukat G, Shagdarsuren E, Plehm R, Brasen JH, Fiebeler A, Schneider W, Caluwaerts S, Vercruysse L, Pijnenborg R, Luft FC, Muller DN. Agonistic autoantibodies to the AT1 receptor in a transgenic rat model of preeclampsia. Hypertension. 2005; 45: 742–746.[Abstract/Free Full Text]
9. Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol. 1988; 158: 892–898.[Medline] [Order article via Infotrieve]
10. Allen J, Tapia-Santiago C. Kutteh Antiphospholipid antibodies in patients with preeclampsia. Am J Reprod Immunol. 1996; 36: 81–85.[Medline] [Order article via Infotrieve]
11. Yamamoto T, Yoshimura S, Geshi Y, Sasamori Y, Mori H, Kobayashi T. Anti-ssDNA and dsDNA antibodies in preeclampsia. Asia Oceania J Obstet Gynaecol. 1994; 20: 93–99.[Medline] [Order article via Infotrieve]
12. Dragun D, Muller DN, Brasen JH, Fritsche L, Nieminen-Kelha M, Dechend R, Kintscher U, Rudolph B, Hoebeke J, Eckert D, Mazak I, Plehm R, Schonemann C, Unger T, Budde K, Neumayer HH, Luft FC, Wallukat G. Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. N Engl J Med. 2005; 352: 558–569.[Abstract/Free Full Text]
13. Meekins JW, Pijnenborg R, Hanssens M, McFadyen IR, van Asshe A. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol. 1994; 101: 669–674.[Medline] [Order article via Infotrieve]
14. Martin AM, Bindra R, Curcio P, Cicero S, Nicolaides KH. Screening for pre-eclampsia and fetal growth restriction by uterine artery Doppler at 11–14 weeks of gestation. Ultrasound Obstet Gynecol. 2001; 18: 583–586.[CrossRef][Medline] [Order article via Infotrieve]
15. Davison JM, Homuth V, Jeyabalan A, Conrad KP, Karumanchi SA, Quaggin S, Dechend R, Luft FC. New aspects in the pathophysiology of preeclampsia. J Am Soc Nephrol. 2004; 9: 2440–2448.

This article has been cited by other articles:

				S. A. Karumanchi and M. D. Lindheimer Preeclampsia Pathogenesis: "Triple A Rating"-Autoantibodies and AntiAngiogenic Factors Hypertension, April 1, 2008; 51(4): 991 - 992. [Full Text] [PDF]

				B. D. LaMarca, J. Gilbert, and J. P. Granger Recent Progress Toward the Understanding of the Pathophysiology of Hypertension During Preeclampsia Hypertension, April 1, 2008; 51(4): 982 - 988. [Full Text] [PDF]

				C. C. Zhou, S. Ahmad, T. Mi, S. Abbasi, L. Xia, M.-C. Day, S. M. Ramin, A. Ahmed, R. E. Kellems, and Y. Xia Autoantibody From Women With Preeclampsia Induces Soluble Fms-Like Tyrosine Kinase-1 Production via Angiotensin Type 1 Receptor and Calcineurin/Nuclear Factor of Activated T-Cells Signaling Hypertension, April 1, 2008; 51(4): 1010 - 1019. [Abstract] [Full Text] [PDF]

				J. S. Gilbert, M. J. Ryan, B. B. LaMarca, M. Sedeek, S. R. Murphy, and J. P. Granger Pathophysiology of hypertension during preeclampsia: linking placental ischemia with endothelial dysfunction Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H541 - H550. [Abstract] [Full Text] [PDF]

				Y. Xia, C. C. Zhou, S. M. Ramin, and R. E. Kellems Angiotensin Receptors, Autoimmunity, and Preeclampsia J. Immunol., September 15, 2007; 179(6): 3391 - 3395. [Abstract] [Full Text] [PDF]

				J. V. Ilekis, U. M. Reddy, and J. M. Roberts Review Article: Preeclampsia A Pressing Problem: An Executive Summary of a National Institute of Child Health and Human Development Workshop Reproductive Sciences, September 1, 2007; 14(6): 508 - 523. [Abstract] [PDF]

				Y. Xia, S. M. Ramin, and R. E. Kellems Potential Roles of Angiotensin Receptor-Activating Autoantibody in the Pathophysiology of Preeclampsia Hypertension, August 1, 2007; 50(2): 269 - 275. [Full Text] [PDF]

				H. Stepan and T. Walther Questionable Role of the Angiotensin II Receptor Subtype 1 Autoantibody in the Pathogenesis of Preeclampsia Hypertension, July 1, 2007; 50(1): e3 - e3. [Full Text] [PDF]

				R. Dechend Response to Questionable Role of the Angiotensin II Receptor Subtype 1 Autoantibody in the Pathogenesis of Preeclampsia: There Is No Single Universal Preeclampsia Cause Hypertension, July 1, 2007; 50(1): e4 - e4. [Full Text] [PDF]

				H. Stepan, A. Unversucht, N. Wessel, and R. Faber Predictive Value of Maternal Angiogenic Factors in Second Trimester Pregnancies With Abnormal Uterine Perfusion Hypertension, April 1, 2007; 49(4): 818 - 824. [Abstract] [Full Text] [PDF]

				C. A. Hubel, G. Wallukat, M. Wolf, F. Herse, A. Rajakumar, J. M. Roberts, N. Markovic, R. Thadhani, F. C. Luft, and R. Dechend Agonistic Angiotensin II Type 1 Receptor Autoantibodies in Postpartum Women With a History of Preeclampsia Hypertension, March 1, 2007; 49(3): 612 - 617. [Abstract] [Full Text] [PDF]

				C. C. Zhou, S. Ahmad, T. Mi, L. Xia, S. Abbasi, P. W. Hewett, C. Sun, A. Ahmed, R. E. Kellems, and Y. Xia Angiotensin II Induces Soluble fms-Like Tyrosine Kinase-1 Release via Calcineurin Signaling Pathway in Pregnancy Circ. Res., January 5, 2007; 100(1): 88 - 95. [Abstract] [Full Text] [PDF]

				J. M. Roberts and F. Von Versen-Hoeynck Maternal Fetal/Placental Interactions and Abnormal Pregnancy Outcomes Hypertension, January 1, 2007; 49(1): 15 - 16. [Full Text] [PDF]

				E. Shibata, R. W. Powers, A. Rajakumar, F. von Versen-Hoynck, M. J. Gallaher, D. L. Lykins, J. M. Roberts, and C. A. Hubel Angiotensin II decreases system A amino acid transporter activity in human placental villous fragments through AT1 receptor activation Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E1009 - E1016. [Abstract] [Full Text] [PDF]

				H. Stepan, R. Faber, N. Dornhofer, B. Huppertz, A. Robitzki, and T. Walther New Insights into the Biology of Preeclampsia Biol Reprod, May 1, 2006; 74(5): 772 - 776. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 46/6/1275    most recent 01.HYP.0000190040.66563.04v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Walther, T. Articles by Stepan, H. Search for Related Content PubMed PubMed Citation Articles by Walther, T. Articles by Stepan, H. Pubmed/NCBI databases Medline Plus Health Information High Risk Pregnancy