In Aged Females, the Enhanced Pressor Response to Angiotensin II Is Attenuated By Estrogen Replacement via an Angiotensin Type 2 Receptor-Mediated Mechanism

Abstract

Loss of ovarian hormones following menopause contributes to the rise in cardiovascular risk with age. Estrogen plays a protective role against hypertension and end-organ damage by modulating the depressor actions of the AT 2 R (angiotensin type 2 receptor). Our aim was to determine whether estrogen replacement in aged female mice can lower arterial pressure, improve endothelial function, and reduce organ fibrosis via an AT 2 R-mediated mechanism. Mean arterial pressure was measured via radiotelemetry in ovary-intact adult (3–4-month-old), aged (16–18-month-old; reproductively senescent) and aged–17β-estradiol (E 2 )–treated (3 µg/day SC) female mice, which were administered vehicle, Ang II (angiotensin II; 600 ng/[kg·min] SC) or Ang II+PD123319 (AT 2 R antagonist; 3 mg/[kg·day SC). On day 21 of treatment, aortic endothelium-dependent relaxation and cardiac and renal tissue (fibrosis and gene expression) were analyzed. Basal mean arterial pressure was lower in E 2 -treated aged mice (89±1 mm Hg, n=20) relative to aged controls (94±1 mm Hg; n=18, P =0.002). The Ang II pressor response was enhanced by ≈20 mm Hg in aged compared with adult females ( P =0.01). E 2 -treatment reduced the Ang II pressor response in aged females ( P =0.002), an effect that was reversed by PD123319 in the aged E 2 –Ang II group ( P =0.0009). E 2 -treatment increased renal AT 2 R (≈6-fold; P <0.0001) and MasR (Mas oncoreceptor; 2–3-fold, P <0.05) gene expression in aged females. However, neither Ang II–induced endothelial dysfunction nor the age-related increase in renal and cardiac fibrosis was restored by E 2 -treatment in aged female mice. In conclusion, estrogen replacement in aged females may reduce arterial pressure to levels observed in adult females, via an AT 2 R-mediated renal mechanism.

Loss of the Protective Effect of Estrogen Contributes to Maternal Gestational Hypertension‐Induced Hypertensive Response Sensitization Elicited by Postweaning High‐Fat Diet in Female Offspring

“…This effect was associated with upregulation of renal AT2‐R, which was abrogated by AT2‐R antagonism. 39 In the present study, MHT and HFD upregulated mRNA expression of the Mas‐R and IL‐10, an antihypertensive cytokine, in the PVN of intact female offspring. Especially, the expression of AT2‐R was upregulated in HFD fed offspring of normotensive dams but not of hypertensive dams, suggesting that the effect of estrogen on the AT2‐R was impaired by MHT.…”

“… 36 , 37 , 38 Another RAS antihypertensive pathway involving ANG II and the AT2‐R can also potentially mediate estrogen protection against ANG II– or aldosterone‐induced hypertension in female animals. 39 , 40 , 41 Estrogen replacement, in aged, reproductively senescent female mice, blunted the pressor response in an ANG II–induced model of hypertension. This effect was associated with upregulation of renal AT2‐R, which was abrogated by AT2‐R antagonism.…”

Sex Differences in the Prevalence, Outcomes and Management of Hypertension

“…It has recently been demonstrated that Ang II-mediated pressor responses are ameliorated via angiotensin type 2 receptor (AT 2 R) activation in female but not male murine models [25,26]. Importantly, this depressor effect is lost with age and reproductive senescence and restored following oestrogen replacement [27]. This response was associated with the upregulation renal AT 2 R expression, suggesting that the modulation of blood pressure in this setting occurred via a AT2R-mediated renal mechanism.…”

Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

“…Using the four-core genotype model, where the Sry gene is translocated to chromosome 3, making it possible to differentiate between effects that are sex hormone and/or sex chromosome complement dependent ( Pessôa et al, 2015 ), it has been demonstrated that the X chromosome increases renal AT 2 receptor expression ( Dadam et al, 2017 ). Furthermore, numerous animal studies have demonstrated that renal AT 2 receptor expression is greater in females than in males ( Hilliard et al, 2014 ; Mirabito et al, 2014 ) and that this effect is linked to either estrogen, ovarian hormones, or reproductive status ( Mirabito et al, 2014 ; Barsha et al, 2021 ). Thus, the AT 2 receptor may contribute to the relative cardiorenal protection observed in adult females compared with age-matched males and reproductively senescent (e.g., postmenopausal) females.…”

“…There is evidence to suggest that the enhanced functional role of renal AT 2 receptors in females diminishes with age. In association with a reduction in renal AT 2 receptor expression, the chronic pressure-natriuresis relationship is shifted rightward ( Mirabito et al, 2014 ) and the hypertensive response to Ang II is enhanced ( Barsha et al, 2021 ) in aged reproductively senescent females compared with their adult counterparts. In these studies, genetic or pharmacological AT 2 receptor deficiency did not alter the response in the aged females.…”