Abstract
BackgroundThe pressor response to angiotensin II (AngII) is attenuated in adult females as compared to males via an angiotensin type 2 receptor (AT2R)-dependent pathway. We hypothesized that adult female mice are protected against AngII-induced hypertension via an enhanced AT2R-mediated pathway and that in reproductively senescent females this pathway is no longer operative.MethodsMean arterial pressure was measured via telemetry in 4-month-old (adult) and 16-month-old (aged) and aged ovariectomized (aged-OVX) wild-type and AT2R knockout (AT2R-KO) female mice during baseline and 14-day infusion of vehicle (saline) or AngII (600 ng/kg/min s.c.). Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to determine renal gene expression of angiotensin receptors and angiotensin-converting enzyme 2 in response to 14-day treatment with vehicle or AngII.ResultsBasal mean arterial pressure was similar between the groups. The pressor response to AngII was augmented in adult AT2R-KO compared to adult wild-type mice (29 ± 3 mmHg versus 10 ± 4 mmHg, respectively, on day 14 as compared to basal mean arterial pressure, P = 0.002). In wild-type mice, pressor responsiveness to AngII was augmented with age, such that the pressor response to AngII was similar between aged AT2R-KO and wild-type female mice (31 ± 4 mmHg versus 34 ± 3 mmHg, respectively, on day 14, P = 0.9). There were no significant differences in pressor responsiveness to AngII between aged and aged-OVX mice. Vehicle-treated aged wild-type mice had a lower renal AT2R/AT1R balance as compared to adult counterparts. In response to AngII, the renal AT2R/AT1R balance in aged wild-type females was greater than that observed in vehicle-treated aged wild-type females and adult wild-type females, yet the protective effects of AT2R activation were not restored.ConclusionsThe protective role of the AT2R depressor pathway is lost with age in female mice. Therefore, targeting deficits in AT2R expression and/or signaling may represent a novel anti-hypertensive approach in aged females.
Highlights
The pressor response to angiotensin II (AngII) is attenuated in adult females as compared to males via an angiotensin type 2 receptor (AT2R)-dependent pathway
We have previously demonstrated that this sex difference in pressor responsiveness to AngII is associated with higher renal AT2R expression in females as compared to males [3,4]
There were no differences in basal hemodynamics, locomotor activity or body weight between the animals that were allocated to vehicle or AngII treatment
Summary
The pressor response to angiotensin II (AngII) is attenuated in adult females as compared to males via an angiotensin type 2 receptor (AT2R)-dependent pathway. The RAS depressor pathways are thought to play a protective role in the setting of arterial pressure in adult females of reproductive age [6,7]. AT2R deficiency increases the pressor responsiveness to AngII in adult female mice to a similar extent to that observed in agematched male mice [4]. These data indicate that the AT2R plays a central role in the attenuated pressor response to AngII-induced hypertension in females. Given that AT2R expression is estrogen dependent [3,4,5], it is plausible that reproductive senescence may lead to lower AT2R expression and, in turn, increased pressor responsiveness to AngII in aged females
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