Endothelin-1, Oxidative Stress, and Endogenous Angiotensin II

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 (MAP) and renal vascular sensitivity to ANGII during pregnancy. First, we examined MAP and renal artery resistance index (RARI) in response to chronic administration of ANGII or AT1-AA or AT1-AA+ANGII in pregnant rats compared to control pregnant rats. In order 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, Endothelin-1 and oxidative stress in AT1-AA+ANGII treated rats. Chronic ANGII increased MAP from 95 +/−2 in NP rats to 115 +/−2 mmHg. Chronic AT1-AA increased MAP to 118+/−1 mmHg in NP rats which further increased to 123+/−2 with AT1-AA+ANGII. Increasing ANGII from (10−11-10−8) decreased Af-Art diameter 15-20% but sharply decreased Af-Art diameter 60% in AT1-AA pretreated vessels. RARI increased from 0.67 in NP 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 ET-1 and ROS increased with AT1-AA+ANGII compared to AT1-AA alone and blockade of either of these pathways had significant effects on MAP or RARI. These data support the hypothesis that AT1-AA, via activation of ET-1 and oxidative stress and interaction with endogenous ANGII, are important mechanisms whereby MAP and renal vascular responses are enhanced during preeclampsia.

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

“…Another possibility is that pathophysiological levels of ET-1 (or ET-1 ) and/or heightened expression of ET A receptors on vascular smooth muscle lead to overactivation of ET A receptors, thus overwhelming the physiological activation of the endothelial ET B -NO vasodilatory pathway by RLN, leading to renal vasoconstriction. Circulating AT1-AA could directly agonize the AT1 receptor on the afferent arteriole and synergize with circulating AII, thereby impairing renal function (19). Furthermore, this synergy may contribute to the increase in systemic AII pressor response in PE (76,201).…”

Vitamin D supplementation improves pathophysiology in a rat model of preeclampsia

“…Furthermore, AT 1 -AA and sFlt-1 play a significant role in the development of endothelial dysfunction and hypertension in PE and have been found to correlate with PE severity in patients (15,25,30,43,60,64,65,67,69,71,72). AT 1 -AA infusion induces many pathophysiological characteristics of PE, including increased blood pressure, vascular resistance, ET-1, and sFlt-1 (8,35). Although the contribution of immune factors in the pathogenesis of preeclampsia is well established, immune therapy in preeclamptic women is limited by the potential for teratogenic effects of many anti-inflammatory and antihypertensive drugs.…”

Genetic and Potential Autoimmune Triggers of Primary Aldosteronism

“…Moreover, infusion of AT 1 -AA into pregnant rats induced a hypertensive response that seemed to be via an endothelin-1-dependent mechanism. 45,46 In another study, injection of AT 1 -AA into pregnant rats induced symptoms consistent with preeclampsia, including hypertension, proteinuria, and intrauterine growth retardation that was associated with the upregulation of hypoxia-inducible factor-1α and endothelin-1. 47 In this case, however, the phenotypic effect was only observed when the antibody transfer was performed in combination with angiotensin II, 47 that is, not when transferred alone as in other studies.…”

“…47 In this case, however, the phenotypic effect was only observed when the antibody transfer was performed in combination with angiotensin II, 47 that is, not when transferred alone as in other studies. 45,46 Therefore, a wealth of studies have demonstrated a key role for AT 1 -AA in the pathophysiology of preeclampsia. The efficacy of the AFHYESQ epitope-blocking peptide in abolishing the AT 1 -AA functional response has been established, thus raising the possibility of epitope peptide therapy as a tenable therapeutic strategy to treat preeclampsia.…”