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

Abstract

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.

Keywords: angiotensin II; preeclampsia.

Figure 1. AT1-AA interacts with ANGII to increase blood pressure and enhance renal vasoconstriction during pregnancy

Chronic infusion of ANGII or AT1-AA alone increases blood pressure significantly above that of NP rats. Combination of AT1-AA+ANGII chronic infusion causes an even greater blood pressure response in pregnant rats. Chronic infusion of AT1-AA increases renal artery resistive index significantly above that of NP rats. Combination of AT1-AA+ANGII chronic infusion causes an even greater resistive index than AT1-AA or ANGII alone. Significance equal P<0.05, compared to NP.

Figure 2. AT1-AA blocking peptide blunts AT1-AA-enhanced ANGII- induced afferent arteriolar constriction

Administration of non constrictor doses of ANGII or AT1-AA has no effect on aft art isolated from pregnant rats. However combination of AT1-AA+ANGII has profound constrictor effects that are significantly blunted by an AT1-AA seven amino acid blocking peptide. Signiciance equals P<0.05 compared to baseline.

Figure 3. Tissue levels of PPET-1 are increased with AT1-AA+ANGII

AT1-AA+ANGII increased ET-1 transcript in the renal cortices and aorta of pregnant rats Significance equal P<0.05, compared to NP.

Figure 4. Placental oxidative stress is further exacerbated with AT1-AA+ANGII

AT1-AA stimulated placental oxidative stress much greater than ANGII compared to normal pregnant rats. This response was even greater in rats treated with both AT1-AA+ANGII Significance equal P<0.05, compared to NP.

Figure 5. ET-1 and ROS play an important to enhance renal and blood pressure sensitivity to ANGII during pregnancy

MAP blunted in the presence of ETA. (*) indicates significant differnce compared to AT1-AA+ANGII (p<0.05). Surprisingly, the RARI was unchanged in animals exposed to both AngII and AT1-AA when given ETA in their drinking water. This did not reach statistical significance.The addition of Tempol to the drinking water of rats exposed to AngII and AT1-AA was noted to blunt the hypertesive response though this difference did not reach statistical significance. Tempol did however, normalize the RARI seen with AT1-AA+ANGII. (*) indicates significant difference compared to AT1-AA+ANGII (p<0.05).

Figure 6. AT1-AA increased blood pressure independent of endogenous ANGII

Enalapril decreased blood pressure in NP rats. In addtion Enalapril blunted the rise in blood pressure normally seen in response to chronic AT1-AA infusion. However, the blood pressure response to AT1-AA in the presence of Enalapril was still significantly greater than that of NP treated with Enalapril. (* denotes P< 0.05).