Role of Inflammation and the Angiotensin Type 2 Receptor in the Regulation of Arterial Pressure During Pregnancy in Mice

Abstract

Abstract-During normal pregnancy the renin-angiotensin system is activated, yet pregnant women are resistant to the pressor effects of angiotensin II. Our aim was to determine the role of the angiotensin type 2 receptor (AT 2 R) in the regulation of arterial pressure, natriuresis, and immune cell infiltration during pregnancy. Mean arterial pressure was measured via telemetry, and flow cytometry was used to enumerate immune cell infiltration in 14-week-old wild-type and AT 2 R knockout mice during gestation. In wild-type mice, mean arterial pressure decreased during gestation, reaching a nadir at gestational day 9 (-6±2 mm Hg) and returned to near preconception levels during late gestation. In AT 2 Rdeficient mice, the midgestational decrease in mean arterial pressure was absent. Furthermore, mean arterial pressure was significantly increased during late gestation compared with wild-type mice (≈10 mm Hg). As expected, circulating immune cell activation was suppressed during pregnancy. However, this response was absent in AT 2 R-deficient mice. While renal immune cell infiltration was similar between the genotypes, there was a significant T cell phenotypic switch toward a proinflammatory T-helper 1 phenotype in AT 2 R-deficient mice. These data indicate that the AT 2 R plays an important role in arterial pressure regulation and may modulate T cell activation and renal cytokine production during pregnancy. Therefore, deficits in AT 2 R expression may contribute to pregnancy-induced hypertension and thus represents a potential therapeutic target.

Brain endogenous angiotensin II receptor type 2 (AT2-R) protects against DOCA/salt-induced hypertension in female rats

“…Denton et al recently demonstrated a key role for the AT2-R in the normal regulation of BP during pregnancy. AT2-R deficiency resulted in a phenotypic switch in the T cells infiltrating the kidney toward a proinflammatory phenotype, thereby increasing the BP during late gestation [48]. These results suggest that estrogen can interact with AT2-R to improve neural and cardiovascular function through their anti-inflammatory effect.…”

Central Infusion of Angiotensin II Type 2 Receptor Agonist Compound 21 Attenuates DOCA/NaCl‐Induced Hypertension in Female Rats

“…This depressor effect of ANG II in females is via an AT2-R-mediated and an estrogen-dependent mechanism [ 15 ]. Moreover, the AT2-R mediates the normal midgestational decrease in BP and contributes to BP regulation during late gestation [ 16 ]. These findings suggest that the BP is differentially regulated by the AT2-R in females as compared with males and support an enhanced role for AT2-R in regulating BP in females.…”

“…Downregulation of renin-angiotensin system (RAS) hypertensive components, upregulation of RAS antihypertensive components, and anti-inflammation have been shown to be important features of the AT2-R underlying improved outcome in experimental disease models [ 16 – 23 ]. Our previous study has demonstrated that central blockade of AT2-R augments deoxycorticosterone acetate (DOCA)/NaCl-induced pressor effect in females through modulating expression of RAS components and proinflammatory cytokines in the PVN [ 24 ].…”

High-Dose Estradiol-Replacement Therapy Enhances the Renal Vascular Response to Angiotensin II via an AT2-Receptor Dependent Mechanism

“…Evidence also suggests that arterial pressure is kept normal during pregnancy by a decreased vascular responsiveness to Ang II modulated in part by upregulation of AT 2 R expression. This was demonstrated in AT 2 R null mice in which arterial pressure rose significantly during pregnancy [ 38 ]. Finally, Ang II caused dose-dependent forearm vasodilatation in female patients following 3-week candesartan treatment; and PD123319 infusion elevated baseline forearm vascular resistance, suggesting that tonic AT 2 R-mediated vasodilatation contributes to the hemodynamic profile of AT 1 R blockade [ 39 ].…”