Endothelin-1, oxidative stress, and endogenous angiotensin II: mechanisms of angiotensin II type I receptor autoantibody-enhanced renal and blood pressure response during pregnancy


  • J. Brewer
  • R. Liu
  • Y. Lu
  • J. Scott
  • K. Wallace
  • G. Wallukat
  • J. Moseley
  • F. Herse
  • R. Dechend
  • J.N. Martin
  • B. Lamarca


  • Hypertension


  • Hypertension 62 (5): 886-892


  • Hypertension during preeclampsia is associated with increased maternal vascular sensitivity to angiotensin II (ANGII). This study was designed to determine mechanisms whereby agonistic autoantibodies to the ANGII type I receptor (AT1-AA) enhance blood pressure (mean arterial pressure [MAP]) and renal vascular sensitivity to ANGII during pregnancy. First, we examined MAP and renal artery resistance index in response to chronic administration of ANGII or AT1-AA or AT1-AA+ANGII in pregnant rats compared with control pregnant rats. To examine mechanisms of heightened sensitivity in response to AT1-AA during pregnancy, we examined the role of endogenous ANGII in AT1-AA-infused pregnant rats, and that of endothelin-1 and oxidative stress in AT1-AA+ANGII-treated rats. Chronic ANGII increased MAP from 95+/-2 in normal pregnant rats to 115+/-2 mm Hg; chronic AT1-AA increased MAP to 118+/-1 mm Hg in normal pregnant rats, which further increased to 123+/-2 mm Hg with AT1-AA+ANGII. Increasing ANGII from 10(-11) to 10(-8) decreased afferent arteriole diameter from 15% to 20% but sharply decreased afferent arteriole diameter to 60% in AT1-AA-pretreated vessels. Renal artery resistance index increased from 0.67 in normal pregnant rats to 0.70 with AT1-AA infusion, which was exacerbated to 0.74 in AT1-AA+ANGII-infused rats. AT1-AA-induced hypertension decreased with enalapril but was not attenuated. Both tissue endothelin-1 and reactive oxygen species increased with AT1-AA+ANGII compared with AT1-AA alone, and blockade of either of these pathways had significant effects on MAP or renal artery resistance index. These data support the hypothesis that AT1-AA, via activation of endothelin-1 and oxidative stress and interaction with endogenous ANGII, is an important mechanism whereby MAP and renal vascular responses are enhanced during preeclampsia.