(Circulation. 2000;101:2382.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
AT1 Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor
From Franz Volhard Clinic and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin (Germany) (R.D., V.H., J.-K.P, J.T., D.C.G., H.H., F.C.L); the Department of Obstetrics and Gynecology, Klinikum Buch, Berlin, Germany (A.J.); the Department of Internal Medicine III, University of Heidelberg (Germany) (J.K.); and the Department of Immunology and Vascular Biology, Scripps Institute, La Jolla, Calif (N.M.).
Correspondence to Friedrich C. Luft, Franz Volhard Clinic, Charité Campus-Buch, Wiltberg Strasse 50, 13125 Berlin, Germany. E-mail luft{at}fvk-berlin.de
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Abstract |
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Background—We recently described autoantibodies (angiotensin-1 receptor autoantibodies, AT1-AA) directed at the AT1 receptor in the serum of preeclamptic patients, whose placentas are commonly infarcted and express tissue factor (TF). Mechanisms of how AT1-AA might contribute to preeclampsia are unknown. We tested the hypothesis that AT1-AA cause vascular smooth muscle cells (VSMC) to express TF.
Methods and Results—IgG from preeclamptic patients containing AT1-AA was purified with anti-human IgG columns. AT1-AA were separated from the IgG by ammonium sulfate precipitation. We transfected Chinese hamster ovary cells overexpressing the AT1 receptor with TF promoter constructs coupled to a luciferase reporter gene. VSMC were obtained from human coronary arteries. Extracellular signal-related kinase activation was detected by an in-gel kinase assay. AP-1 activation was determined by electromobility shift assay. TF was measured by ELISA and detected by immunohistochemistry. Placentas from preeclamptic women stained strongly for TF, whereas control placentas showed far less staining. We proved AT1-AA specificity by coimmunoprecipitating the AT1 receptor with AT1-AA but not with nonspecific IgG. Angiotensin (Ang) II and AT1-AA both activated extracellular signal-related kinase, AP-1, and the TF promoter transfected VSMC and Chinese hamster ovary cells, but only when the AP-1 binding site was present. We then demonstrated TF expression in VSMC exposed to either Ang II or AT1-AA. All these effects were blocked by losartan. Nonspecific IgG or IgG from nonpreeclamptic pregnant women had a negligible effect.
Conclusions—We conclude that AT1-AA and Ang II both stimulate the AT1 receptor and initiate a signaling cascade resulting in TF expression. These results show an action of AT1-AA on human cells that could contribute to the pathogenesis of preeclampsia.
Key Words: angiotensin • receptors • muscle, smooth • pregnancy
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Introduction |
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Preeclampsia occurs after the 20th week of gestation and features hypertension and an increased peripheral vascular resistance; the mechanisms are unknown. The condition occurs in 5% to 10% of pregnancies and is a major cause of maternal and fetal death.1 Endothelial dysfunction plays an important role in the disorder.2 3 Evidence has been presented that an as-yet unidentified circulating factor(s) is released into the maternal circulation, which leads to endothelial cell activation and subsequently to endothelial dysfunction.4 Studies of sera from preeclamptic patients have shown that cultured endothelial cells respond with increased expression of growth factors, fibronectin, oxygen free radical production, and inhibition of prostacyclin production.5 6 7 8 9 We showed earlier that serum from preeclamptic women stimulates surface adhesion molecule expression and increases endothelial celllayer permeability.10 11 Recently, we observed that circulating antibodies to a vascular receptor might be responsible for the hypertension observed in preeclampsia.12 We found that the IgG fraction from preeclamptic women contains an angiotensin-1 receptor autoantibody (AT1-AA) that stimulates the AT1 receptor. Placentas from preeclamptic women exhibit relative placental insufficiency, placental infarctions, and increased tissue factor (TF) expression compared with placentas from normal pregnancies.13 We therefore tested the hypothesis that AT1-AA might cause vascular cells to express TF.
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Methods |
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Preparation of Immunoglobulin Fraction
We used IgG fractions from preeclamptic women containing AT1-AA. Preparation of the IgG fraction is outlined in detail elsewhere.14 Briefly, affinity purification was performed. The immunoglobulin fractions from the patients were loaded on a Sepharose 4B CNBr–activated gel (Pharmacia), to which the peptide corresponding to the second extracellular loop of the human AT1 receptor was covalently linked. The antibodies were eluted with 3 mol/L potassium thiocyanate (pH 7.4) followed by immediate extensive dialysis against PBS. The AT1-AA were prepared from the sera of 12 preeclamptic women, diagnosed according to criteria outlined elsewhere.12 These criteria rely on documenting no hypertension before pregnancy, no proteinuria before the second trimester, and proteinuria after the 20th week of pregnancy with increased blood pressure. IgG from preeclamptic women after AT1-AA had been eluted, was used as a negative control, and is termed "nonspecific" IgG. We also had control IgG from 12 healthy nonpreeclamptic pregnant women who had not participated in our earlier studies. Written informed consent was obtained.
Cell Culture
We used human coronary artery vascular smooth muscle
cells (VSMC) in this study because of their reliable expression of the
AT1 receptor. VSMC were obtained from Clonetics
and were grown in SmGM2 medium (Clonetics). Chinese hamster ovary (CHO)
cells overexpressing the AT1 receptor and CHO
wild-type cells in DMEM/HAMs F-12 containing geneticine (63 mg/L), 10%
FCS, 0.1% penicillin/streptomycin, and glutamine. Cells were grown to
75% confluence.
Immunohistochemistry
Immunohistochemistry was done on cryosections with the use of
standard peroxidase-antiperoxidase techniques as described
earlier.10 Endogenous peroxidase was
inactivated by immersing the sections in methanol
containing 0.6% H2O2 for
10 minutes. After the standard steps, the sections were developed in
3-amino-ethylcarbazole until a red/brown reaction product could be
seen. Finally, counterstaining was performed with Mayer’s hemalaum
(Merck). Preparations were examined under a Zeiss Axioplan-2
microscope. Fifteen different areas of each placenta sample were
analyzed. The placenta samples were examined without knowledge
of the disease identity. The antibody against human TF was a kind gift
of Dr Luther, University of Dresden (Germany).
Extracellular Signal-Related Kinase Assay
VSMC were set serum free for 24 hours and stimulated with
Angiotensin (Ang) II, AT1-AA, or
nonspecific IgG for 15 minutes. After stimulation, cells were harvested
by aspirating the medium and washing twice with PBS (4°C). Cells were
lysed by addition of lysis buffer (4°C: 20 mmol/L Tris-HCl, pH
7.4, 150 mmol/L NaCl, 1 mmol/L EDTA, 1 mmol/L EGTA, 1%
Triton, 2.5 mmol/L sodium pyrophosphate, 1 mmol/L
Na3VO4, 1 µg/mL
leupeptin, 1 mmol/L phenylmethylsulfonyl fluoride),
scraped off the dish, sonicated, and centrifuged (13 000 rpm,
4°C, 10 minutes). Protein concentrations were determined with the use
of a bicinchoninic acid protein assay kit from Pierce, according to the
manufacturer’s protocol.14 Cell lysates were separated by
SDS-PAGE and transferred to nitrocellulose membranes. The membranes
were blocked (room temperature [RT] 1 hour; TBST (1xTris-buffered
saline plus 0.1% Triton X-100): 20 mmol/L Tris-HCl, pH 7.4,
150 mmol/L NaCl, and 0.05% Tween 20, 5% BSA) and then incubated
with the phospho–extracellular signal-related kinase (ERK)1/2 antibody
(New England Biolabs) for 1 hour at RT followed by incubation with the
secondary peroxidase-conjugated antibody (1 hour RT). The proteins were
detected with the use of an enhanced chemiluminescence detection system
(Amersham)
Electromobility Shift Assay
Tissue extracts and electromobility shift assay (EMSA) were
performed as described earlier.15 Double-stranded
oligonucleotides containing the consensus sequence for
AP-1 (Santa Cruz Biotechnology Inc, 5'-GAT CCA GGG CTG GGG ATT CCC CAT
CTC CAC AGG) were radiolabeled with gamma-32P
with the use of T4 polynucleotide kinase by standard
methods and purified over a column. Antibodies directed against
c-Jun, c-Myb, and nuclear factor (NF)-
B (P65)
were obtained from Santa Cruz Biotechnology Inc.
Transfection Experiments
The human TF luciferase promoters have been described
previously16 and included the promoters of TF (-244 to
+1) and TF (-111 to +1). For transient transfection, 2 µg of the
appropriate luciferase promoter construct per milliliter of medium was
transfected with Fugene6 (Roche Boehringer) according to the
manufacturer’s description. Transfected cells were stimulated for 15
minutes with no or 10-7 mol/L Ang II.
AT1 receptor was blocked by a 30-minute
preincubation with 10-5 mol/L losartan.
Cells were harvested and lysed as described earlier.17
Relative luciferase units were calculated as percentage of basal
luciferase activity of the nonstimulated cell line. The measurements
were performed in duplicate. The data were confirmed in 3 to 5
independent transfections. For these studies, separate transfections
were performed from 7 preeclamptic women and 7 control women.
Coimmunoprecipitation
VSMC were lysed in modified RIPA lysate buffer containing
50 mmol/L Tris (pH 8.0), 150 mmol/L NaCl, 20% glycerol,
1 mmol/L MgCl2, 0.5 mmol/L EDTA,
0.1 mmol/L EGTA, 1% NP-40, 1% Na-desoxycholate, 0.2% SDS, and
protease inhibitors. Cell lysates, 20 µL staphylococcal
protein A–sepharose beads (50% slurry, Promega), and the indicated
antiserum were incubated at 4°C for 2 hours. Precipitates were washed
with RIPA buffer 6 times, subjected to SDS-PAGE, blotted to the
PVDF (polyvinylidene fluoride resin) membrane, and
probed with the indicated antiserum. Antibody binding was revealed with
the use of enhanced chemiluminescence detection (Amersham).
Anti-AT1, anti–interleukin-1 receptor, and
anti-human antibodies were obtained from Santa Cruz Biotechnology
Inc.
TF Activity
Protein concentrations of the cellular extracts were quantified
by use of the Bradford method.18 TF activity was
determined in cell extracts with a clotting-based assay according to
the manufacturer’s instructions (ACTICLOT, Diagnostics
International). Data and standard deviations represent means of
triplicates.
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Results |
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Figure 1
shows immunohistochemistry
of 2 placentas, one from a normal pregnancy and one from a patient with
preeclampsia. An antibody against TF, followed by a second antibody
coupled with peroxidase, was applied. Strongly positive staining is
seen in the preeclamptic placenta. The upper panel shows
cytotrophoblasts; lower panels show blood vessels at 2 levels of
magnification. Far more TF is seen in the placental vessel from the
preeclamptic placenta compared with the control placenta.
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Figure 2 shows a series of
coimmunoprecipitations. From the left in lane 1 is the positive
control. Immunoprecipitation with a commercial
AT1 receptor antibody and subsequent
immunoblotting with a different commercial
AT1 receptor antibody directed against a
different AT1 receptor epitope results in the
band as shown at 48 kDa. Lane 2 shows a negative control, in which the
VSMC extracts were exposed to an IL-1 receptor antibody and
immunoblotted with an AT1 receptor
antibody. No band resulted. Lane 3 shows the coimmunoprecipitation
experiment in which VSMC extracts were immunoprecipitated with a
commercial AT1 receptor antibody and
immunoblotted with AT1-AA. A band
results at the same position as lane 1 at 48 kDa. Lane 4 shows that the
coimmunoprecipitations in the earlier lane were specific, since
nonspecific IgG from the same patient failed to react with the
immunoprecipitated AT1 receptor and no band
resulted. Lane 5 shows reciprocal coimmune precipitation, in which the
AT1-AA were used as the immunoprecipitating
antibody and the commercial AT1 antibody as the
detection antibody. To demonstrate specificity, we used nonspecific IgG
from the same patient as the immunoprecipitating antibody in lane 6,
and no band resulted. These experiments show specific binding of the
AT1-AA to the AT1
receptor.
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We next tested whether or not AT1-AA would
initiate the ERK1/2 pathway involved in AP-1 activation. These results
are shown in Figure 3A. Ang II induced
ERK1/2 (p44 and p42), which was diminished by losartan.
AT1-AA also induced ERK1/2, which was inhibited
by losartan. Nonspecific IgG or IgG from nonpreeclamptic women
had a lesser effect. We then tested whether or not
AT1-AA would activate AP-1. Figure 3B shows the EMSA for the AP-1 transcription factor. Lane 1 is
the control lane (left). Lane 2 shows VSMC exposed to Ang II
(1x10-7 mol/L) for 15 minutes. A strong AP-1
band is visible, indicating strong DNA binding activity of AP-1
complexes. Lane 3 shows the same Ang II exposure in the presence of 30
minutes of losartan (1x10-5 mol/L)
preexposure. No AP-1 induction, compared with control, was observed.
Lane 4 shows VSMC exposed to AT1-AA. A band
similar to Ang II exposure was observed. Lane 5 shows the same
preparation with AT1-AA–treated VSMC previously
exposed to losartan. No band induction was observed. Lane 6
shows VSMC exposed to nonspecific IgG from the same patient. No band
induction occurred. Lane 7 shows VSMC exposed to IgG from an
nonpreeclamptic pregnant patient. Again, no band induction was
observed. Figure 3C shows a supershift in lane 3 with antibody
directed against c-Jun. No supershifts were observed with
anti–c-Myb or anti-p65 NF-B antibodies, used as
controls. In lane 6 is shown a competition with unlabeled AP-1,
suggesting specificity of the AP-1 activation.
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We next verified the specificity of our observations by showing that
the AP-1 binding site must be present for Ang II or
AT1-AA–related TF promoter activation. Figure 4 shows luciferase activity on the
ordinate and treatments on the abscissa in VSMC, transfected with 2 TF
promoter constructs. Ang II treatment resulted in full expression of
the intact TF promoter. This effect was fully blocked with
losartan. AT1-AA from a preeclamptic
patient gave a response similar to Ang II. This effect was also blocked
with losartan. Nonspecific IgG from the same patient had no
effect. IgG from a nonpreeclamptic pregnant patient had no effect. When
the experiments were repeated with a TF promoter lacking both AP-1 and
NF-B binding sites, no stimulation was observed with either Ang II
or AT1-AA treatment. The lower panel shows the
same experiment performed in CHO cells expressing the
AT1 receptor. Similar responses were observed. A
wild-type CHO cell line with minimal AT1 receptor
expression but transfected with the full-length TF promoter showed no
effect when exposed to Ang II or AT1-AA
treatment. This experiment documents that the TF promoter activation
resulted from AT1 receptor stimulation.
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NF-
After demonstrating that TF expression is increased in preeclamptic
placentas and can be induced in VSMC, we investigated whether or not TF
is functionally active. Figure 5A shows
TF activity from VSMC extracts exposed to various treatments.
Nonstimulated cells showed minimal activity. Ang II exposure increased
TF activity, which was blocked by losartan.
AT1-AA from a preeclamptic patient caused
an effect similar to Ang II exposure. This effect was also blocked by
losartan. Nonspecific IgG from the same patient and IgG from a
nonpreeclamptic pregnant patient generated no TF activity. Figure 5B shows the TF activity measured from a normal placenta and a
preeclamptic placenta. The preeclamptic placenta expressed 6-fold more
TF activity than the normal placenta.
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Discussion |
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We demonstrated by reciprocal coimmunoprecipitation that AT1-AA specifically binds to the AT1 receptor in VSMC. We next showed ERK1/2 phosphorylation and then performed EMSA to show that AP-1 was activated by AT1-AA in a similar fashion as with Ang II. By competition and supershift experiments, we showed that the induced DNA binding activity of AP-1 was specific. The transfection experiments with the TF promoter in VSMC and CHO cells showed that the TF promoter activation was induced by AT1-AA and that the AP-1 binding site must be intact for the activation to occur. We further verified that the induced signal cascade is dependent on the presence of the AT1 receptor, since a cell line not expressing the AT1 receptor showed no induction of the TF promoter in response to either Ang II or AT1-AA. Finally, we showed that AT1-AA–induced TF expression is functionally active in VSMC. Similarly, placentas from preeclamptic patients also expressed TF in increased amounts, compared with that in control subjects. These findings support the notion that increased TF may be functionally relevant.
TF is a 47-kDa transmembrane protein that initiates the extrinsic
pathway of coagulation through formation of an enzymatic complex with
factor VII/factor VIIa.19 However, TF also has biological
functions independent of the clotting cascade in
embryogenesis,20 blood vessel development,21
cell adhesion, and migration.22 The TF promoter is complex
and contains consensus sequences for NF-B and AP-1.23
We focused on AP-1 activation in this study; however, NF-B can also
be activated by Ang II. We performed a supershift
analysis, which demonstrated participation of c-Jun
but not c-Myb or the p65 component of NF-B, supporting
the conclusion that AP-1 is indeed specific. A role for the coagulation
system in the pathogenesis of preeclampsia has been proposed. Oian et
al24 observed increased sensitivity to thromboplastin
synthesis in monocytes from preeclamptic women. Increased
antifibrinolytic activity in placentas from preeclamptic women has been
attributed to plasminogen activator
inhibitor-2.25 Multiple variables of the
hemostatic system from 200 preeclamptic women and 97 control women were
entered into a multivariate regression model and
produced results consistent with activated coagulation
in the placental vessels.26
We believe that AT1-AA from preeclamptic patients may be responsible for TF activation in the placenta and perhaps on endothelial surfaces. Nishimura et al27 have shown that Ang II can stimulate endothelial cells to express TF and plasminogen activator inhibitor-1. How TF expression might participate in the pathogenesis of preeclampsia, other than by promoting local coagulation and perhaps causing ischemia, is unclear. Zhou et al28 recently reported that human cytotrophoblasts adopt a vascular phenotype that appears to be necessary for successful endovascular invasion. In preeclampsia, human cytotrophoblasts fail to express this vascular phenotype.29 Consequently, integrins, cadherins, immunoglobulin superfamily members, and perhaps other structures including surface receptors are not produced appropriately. TF may be important to cell differentiation. Cytotrophoblast differentiation and the maintenance of intervillous flow has been shown to depend on PP5/TFP12, a Kunitz-type proteinase inhibitor, identical to TF inhibitor-2.30 Thus, an influence of TF expression in placental tissue could conceivably influence cytotrophoblast differentiation.
The renin-angiotensin system is implicated in preeclampsia. Gant et al31 identified hypersensitivity to infused Ang II in preeclamptic patients, although the Ang sensitivity test in preeclampsia is not invariably positive.32 Sowers et al33 found elevated active tissue renin concentrations and increased renin mRNA expression in placentas from preeclamptic patients compared with placentas from women with normal pregnancies. Brar et al34 observed increased chorionic tissue active renin levels in patients with preeclampsia compared with that in control subjects. Another line of evidence implicating the renin-angiotensin system in preeclampsia stems from genetic observations, including an association between preeclampsia and the angiotensinogen variant T235,35 and a mutation leading to the replacement of leucine by phenylalanine at position 10 of mature angiotensinogen, the site of renin cleavage.36 We have not yet shown precisely how AT1-AA activate the AT1 receptor, although we have demonstrated the binding site of the antibody.14 Possibly, the AT1-AA do not activate the receptor directly. An alternative mechanism could involve an alteration in the receptor’s configuration, permitting greater accessibility to available Ang II.
In summary, we showed that AT1-AA from IgG of preeclamptic patients specifically coimmunoprecipitated with a commercially available AT1 receptor antibody. AT1-AA induced a signal transduction pathway through the AT1 receptor involving ERK1/2 and AP-1 activation. This cascade of events resulted in TF expression, which was inhibited by AT1 receptor blockade and was not elicited by nonspecific IgG from preeclamptic patients or IgG from healthy pregnant women. Increased TF expression was detected in the placentas of preeclamptic women, raising the possibility that AT1-AA contribute to the pathogenesis of preeclampsia.
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Acknowledgments |
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We thank Karin Dressler, who performed the transfections and the gel mobility shift assays.
Received August 23, 1999; revision received December 10, 1999; accepted December 22, 1999.
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References |
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 M. Mogi, M. Iwai, and M. Horiuchi Emerging Concepts of Regulation of Angiotensin II Receptors: New Players and Targets for Traditional Receptors Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2532 - 2539. [Abstract] [Full Text] [PDF]
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 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]
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 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]
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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]
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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]
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F. Herse, R. Dechend, N. K. Harsem, G. Wallukat, J. Janke, F. Qadri, L. Hering, D. N. Muller, F. C. Luft, and A. C. Staff Dysregulation of the Circulating and Tissue-Based Renin-Angiotensin System in Preeclampsia Hypertension, March 1, 2007; 49(3): 604 - 611. [Abstract] [Full Text] [PDF]
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 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]
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 M. Paul, A. Poyan Mehr, and R. Kreutz Physiology of local Renin-Angiotensin systems. Physiol Rev, July 1, 2006; 86(3): 747 - 803. [Abstract] [Full Text] [PDF]
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R. Dechend, V. Homuth, G. Wallukat, D. N. Muller, M. Krause, J. Dudenhausen, H. Haller, and F. C. Luft Agonistic Antibodies Directed at the Angiotensin II, AT1 Receptor in Preeclampsia Reproductive Sciences, February 1, 2006; 13(2): 79 - 86. [Abstract] [PDF]
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C. Lam, K.-H. Lim, and S. A. Karumanchi Circulating Angiogenic Factors in the Pathogenesis and Prediction of Preeclampsia Hypertension, November 1, 2005; 46(5): 1077 - 1085. [Abstract] [Full Text] [PDF]
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 D. M. Shah Role of the renin-angiotensin system in the pathogenesis of preeclampsia Am J Physiol Renal Physiol, April 1, 2005; 288(4): F614 - F625. [Abstract] [Full Text] [PDF]
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R. Dechend, P. Gratze, G. Wallukat, E. Shagdarsuren, R. Plehm, J.-H. Brasen, A. Fiebeler, W. Schneider, S. Caluwaerts, L. Vercruysse, et al. Agonistic Autoantibodies to the AT1 Receptor in a Transgenic Rat Model of Preeclampsia Hypertension, April 1, 2005; 45(4): 742 - 746. [Abstract] [Full Text] [PDF]
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 D. Dragun, D. N. Muller, J. H. Brasen, L. Fritsche, M. Nieminen-Kelha, R. Dechend, U. Kintscher, B. Rudolph, J. Hoebeke, D. Eckert, et al. Angiotensin II Type 1-Receptor Activating Antibodies in Renal-Allograft Rejection N. Engl. J. Med., February 10, 2005; 352(6): 558 - 569. [Abstract] [Full Text] [PDF]
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 T. M. Thway, S. G. Shlykov, M.-C. Day, B. M. Sanborn, L. C. Gilstrap III, Y. Xia, and R. E. Kellems Antibodies From Preeclamptic Patients Stimulate Increased Intracellular Ca2+ Mobilization Through Angiotensin Receptor Activation Circulation, September 21, 2004; 110(12): 1612 - 1619. [Abstract] [Full Text] [PDF]
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 J. M. Davison, V. Homuth, A. Jeyabalan, K. P. Conrad, S. A. Karumanchi, S. Quaggin, R. Dechend, and F. C. Luft New Aspects in the Pathophysiology of Preeclampsia J. Am. Soc. Nephrol., September 1, 2004; 15(9): 2440 - 2448. [Abstract] [Full Text] [PDF]
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 R. Thadhani, W. P. Mutter, M. Wolf, R. J. Levine, R. N. Taylor, V. P. Sukhatme, J. Ecker, and S. A. Karumanchi First Trimester Placental Growth Factor and Soluble Fms-Like Tyrosine Kinase 1 and Risk for Preeclampsia J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 770 - 775. [Abstract] [Full Text] [PDF]
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 F. C. Luft Pre-eclampsia and the maternal cardiovascular risk Nephrol. Dial. Transplant., May 1, 2003; 18(5): 860 - 861. [Full Text] [PDF]
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R. Dechend, C. Viedt, D. N. Muller, B. Ugele, R. P. Brandes, G. Wallukat, J.-K. Park, J. Janke, P. Barta, J. Theuer, et al. AT1 Receptor Agonistic Antibodies From Preeclamptic Patients Stimulate NADPH Oxidase Circulation, April 1, 2003; 107(12): 1632 - 1639. [Abstract] [Full Text] [PDF]
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Y. Yia, H. Wne, S. Bobst, M.-C. Day, and R. E. Kellems Maternal Autoantibodies From Preeclamptic Patients Active Angiotensin Receptors on Human Trophoblast Cells Reproductive Sciences, February 1, 2003; 10(2): 82 - 93. [Abstract] [PDF]
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 R. A. Khalil and J. P. Granger Vascular mechanisms of increased arterial pressure in preeclampsia: lessons from animal models Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2002; 283(1): R29 - R45. [Abstract] [Full Text] [PDF]
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 Y. Xia, H. Y. Wen, and R. E. Kellems Angiotensin II Inhibits Human Trophoblast Invasion through AT1 Receptor Activation J. Biol. Chem., June 28, 2002; 277(27): 24601 - 24608. [Abstract] [Full Text] [PDF]
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J. M. Roberts Angiotensin-1 Receptor Autoantibodies : A Role in the Pathogenesis of Preeclampsia? Circulation, May 23, 2000; 101(20): 2335 - 2337. [Full Text] [PDF]
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