Pressor responsiveness to angiotensin II in female mice is enhanced with age: Role of the angiotensin type 2 receptor

Abstract

Background: The pressor response to angiotensin II (AngII) is attenuated in adult females as compared to males via an angiotensin type 2 receptor (AT 2 R)-dependent pathway. We hypothesized that adult female mice are protected against AngII-induced hypertension via an enhanced AT 2 R-mediated pathway and that in reproductively senescent females this pathway is no longer operative. Methods: Mean arterial pressure was measured via telemetry in 4-month-old (adult) and 16-month-old (aged) and aged ovariectomized (aged-OVX) wild-type and AT 2 R knockout (AT 2 R-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. Results: Basal mean arterial pressure was similar between the groups. The pressor response to AngII was augmented in adult AT 2 R-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 AT 2 R-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 AT 2 R/AT 1 R balance as compared to adult counterparts. In response to AngII, the renal AT 2 R/AT 1 R 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 AT 2 R activation were not restored. Conclusions: The protective role of the AT 2 R depressor pathway is lost with age in female mice. Therefore, targeting deficits in AT 2 R expression and/or signaling may represent a novel anti-hypertensive approach in aged females.