Hypertension in Response to Autoantibodies to the Angiotensin II Type I Receptor (AT1-AA) in Pregnant Rats

Abstract

Abstract-Agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) and endothelin -1 (ET-1) are suggested to be important links between placental ischemia and hypertension during preeclampsia. Activation of the angiotensin II type 1 receptor (AT1R) increases endothelial cell production of ET-1; however, the importance of ET-1 in response to AT1-AA-mediated AT1 R activation during preeclampsia is unknown. Furthermore, the role of AT1-AA-mediated increases in blood pressure during pregnancy remains unclear. The objective of this study was to test the hypothesis that AT1-AA, increased to levels observed in preeclamptic women and placental ischemic rats, increases mean arterial pressure (MAP) by activation of the ET-1 system. Chronic infusion of purified rat AT1-AA into normal pregnant (NP) rats for 7 days increased AT1-AA from 0.68Ϯ0.5 to 10.88Ϯ1.1 chronotropic units (PϽ0.001). The increased AT1-AA increased MAP from 99Ϯ1 to 119Ϯ2 mm Hg (PϽ0.001). The hypertension was associated with significant increases in renal cortices (11-fold) and placental (4-fold) ET-1. To determine whether ET-1 mediates AT1-AA-induced hypertension, pregnant rats infused with AT1-AA and NP rats were treated with an ET A receptor antagonist. MAP was 100Ϯ1 mm Hg in AT1-AAϩET A antagonist-treated rats versus 98Ϯ2 mm Hg in ET A antagonist-treated rats. Collectively, these data support the hypothesis that one potential pathway whereby AT1-AAs increase blood pressure during pregnancy is by an ET-1-dependent mechanism. Key Words: preeclampsia Ⅲ hypertension Ⅲ kidney Ⅲ placenta Ⅲ inflammation T he initiating event in early onset preeclampsia is postulated to involve inadequate vascularization of the subplacental decidua with reduced placental perfusion that leads to hypertension during pregnancy by mechanisms not yet elucidated. 1,2 Recent studies have suggested that the production of agonistic autoantibodies to the angiotensin II (Ang II) type I receptor (AT1-AA) may be an important link between placental ischemia and hypertension in preeclamptic women. 3-8 The AT1-AA induces signaling in vascular cells that are blocked by an AT1 receptor antagonist including activating protein-1, calcineurin, and nuclear factor kappa B activation. 3,4,7 Recent studies by Zhou et al demonstrate that immunoglobulin isolated from preeclamptic women increases systolic blood pressure 4 days after retro-orbital injection into pregnant mice. 7,8 This hypertensive response was attenuated by administration of an AT1 receptor antagonist. Although these findings suggest that AT1-AAs from preeclamptic women increases blood pressure in pregnant mice, possibly by activation of the AT1 receptor, it remains unclear by what mechanism purified AT1-AA mediates hypertension during pregnancy.We recently reported that hypertension in response to reductions in uterine perfusion pressure in pregnant rats (RUPP) is associated with increased circulating levels of the AT1-AA. 9,10 Moreover, we found that the increased blood pressure response in RUPP pregnant rats decreased ma...

Obstetric Nephrology

“…These results, now confirmed repeatedly by several groups, have elucidated AT 1 R-AA signaling in vascular cells and in placenta, suggesting that it may increase trophoblastic sFlt1 synthesis via a calcineurin-NFAT pathway (46). Animal experiments demonstrate a preeclampsialike syndrome after infusion of AT 1 R-AA in which, surprisingly, hypertension is mediated in part by endothelin 1 (47). Furthermore, several animal models, including surgical uterine hypoperfusion and low-dose TNFa infusion clearly link AT 1 R-AA and sFlt (48).…”

Preeclampsia: Updates in Pathogenesis, Definitions, and Guidelines

“…Interestingly, the same group showed that infusion with an endothelin antagonist in an AT1-AA-infused hypertensive rat was able to decrease its BP. Hence, another possible pathway of AT1-AA-induced hypertension may be via endothelin (56). The fact that transfer of purified human AT1-AA from women with preeclampsia into pregnant mice induced a clinical phenotype of preeclampsia further shows its pathogenicity.…”

Approaching the Threshold for Predicting Preeclampsia

“…In the following years, additional progress has been made with respect to our understanding of the mechanisms underlying the role of antiangiogenic factors in the pathophysiology of preeclampsia. [2][3][4][5][6] Viewed in concert, these studies have clearly established the importance of angiogenic balance in the maintenance of cardiovascular function in normal pregnancy.Despite marked progress toward these ends, the translation of these findings into clinically useful paradigms has moved at a much slower pace. In lieu of the development of novel treatments for preeclampsia, much current attention has been paid to determining the usefulness of these biomarkers for identification of patients who will go on to develop preeclampsia.…”

“…In the following years, additional progress has been made with respect to our understanding of the mechanisms underlying the role of antiangiogenic factors in the pathophysiology of preeclampsia. [2][3][4][5][6] Viewed in concert, these studies have clearly established the importance of angiogenic balance in the maintenance of cardiovascular function in normal pregnancy.…”