Geburtshilfe Frauenheilkd 2006; 66 - PO_G_04_34
DOI: 10.1055/s-2006-952893

Agonistic autoantibodies to the AT1 receptor in rat models of preeclampsia: induced by chronic reductions in uterine perfusion pressure (RUPP) and low dose TNFalpha infusion

S Verlohren 1, F Herse 2, R Pijnenborg 3, G Wallukat 2, JP Granger 4, JW Dudenhausen 1, R Dechend 5
  • 1Klinik für Geburtsmedizin, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin
  • 2HELIOS Klinikum, Charité Campus-Buch & Max-Delbrueck Zentrum, Berlin
  • 3Universitair Ziekenhuis Gasthuisberg, Leuven, Belgium
  • 4Univ. of Mississippi Medical Center, Jackson, USA
  • 5Helios Klinikum, Charité Campus Buch & Max Delbrueck Zentrum, Berlin

Recent studies have found that the IgG fraction from preeclamptic women contains an angiotensin-1 receptor autoantibody (AT1R-AA) that stimulates the angiotensin II type I (AT1) receptor, suggesting that these antibodies could contribute to the pathogenesis of preeclampsia. Therefore, the purpose of this study was to determine whether pregnant rats with chronic reductions in uterine perfusion pressure (RUPP) or low-dose TNFa infusion, develop AT1R-AA. AT1R-AA were detected by the chronotropic responses to AT1 receptor–mediated stimulation of cultured neonatal rat cardiomyocytes coupled with receptor-specific antagonists. Mean arterial pressure (MAP) was significantly higher in RUPP rats (137±1mmHg)) than in normal pregnant (NP) rats (107±1mmHg). The hypertension in the RUPP rats was associated with significant elevations in agonistic antibodies capable of activating the angiotensin AT1 receptor (RUPP, 15.3±1.6 vs. NP, 0.6±0.3 Δbeats/min). Pregnant rats with low dose TNFa infusion (5 days at a rate of 50 ng/d during days 14 to 19 of gestation in pregnant rats) had higher blood pressures (125 + 1mm Hg) than NP rats (101+2mm Hg) also develop AT1R-AA(9.2±2.3 vs. 1.0±0.8 Δbeats/min). Low dose TNFa in virgin rats did not increase MAP or develop AT1R-AA. We also investigated TNFa expression in the placentas of rats with RUPP and could show that TNFa expression is upregulated (p<0.05) Serum TNFa levels were nearly 3fold higher in the RUPP rats compared with NP (p<0.05). In summary, we found that AT1R-AA are present in two different animal models for preeclampsia: the chronic reductions in uterine perfusion pressure (RUPP) and low dose TNFa infusion during pregnancy. We also found that TNFa in the placenta and in the serum is upregulated in the RUPP model. These findings suggest that the generation of AT1R-AA is a secondary event to reduction in placental perfusion leading to chronic inflammation.