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Role of the depressor renin angiotensin system pathways in the regulation of arterial pressure in females
thesisposted on 21.02.2017, 04:55 by Mirabito, Katrina Maree
Sex differences exist in the prevalence of cardiovascular disease (CVD) and its leading risk factor, hypertension. Relative to age-matched men, premenopausal women have lower arterial pressure and are protected from CVD. However, the prevalence of hypertension in postmenopausal women matches or exceeds that observed in men. This indicates that female sex hormones protect against increases in arterial pressure. Accumulating evidence indicates that the sex hormones, testosterone and estrogen, differentially modulate the renin angiotensin system (RAS), which is a long-term regulator of arterial pressure and renal function. Previous findings suggest that females of reproductive age respond differently to the activation of the RAS. In particular, estrogen has been demonstrated to increase components of the depressor RAS pathways, which encompasses the angiotensin type 2 receptor (AT₂R) and the angiotensin converting enzyme 2/Angiotensin-(1-7)/Mas receptor axis. The experiments performed in this thesis examined the contribution of the depressor RAS pathways in the regulation of arterial pressure during two physiological situations that are unique to females and are characterised by hormonal changes; pregnancy and reproductive senescence. In chapter 3 we demonstrated that the AT₂R facilitates the normal mid-gestational decrease in arterial pressure and that AT₂R deficiency increases arterial pressure during late gestation. We also identified a novel role for the AT₂R in the normal suppression of the immune system during pregnancy. Further, deficits in AT2R expression were associated with increases in both renal immune system activation and albuminuria. These abnormal adaptations to pregnancy in AT₂R deficient mice are consistent with the characteristics of preeclampsia. This suggests that the AT₂R plays a key role in the normal cardiovascular and renal adaptations to pregnancy. In chapters 4 and 5, we investigated the role of the depressor RAS pathways in the regulation of arterial pressure in aged reproductively senescent females. We observed that the chronic pressure-natriuresis relationship of adult female mice was shifted leftward such that females excreted the same amount of sodium as males but at a lower arterial pressure. Furthermore, in adult females, but not aged females, absence of the AT₂R was associated with a rightward shift of the chronic pressure-natriuresis relationship. We also observed that the AT₂R attenuates pressor responsiveness to angiotensin II in adult female mice. However, with age and reproductive senescence, female mice have enhanced pressor responsiveness to angiotensin II, which is similar to that observed in female AT₂R deficient mice. These studies also demonstrated that reproductively senescent mice have greater renal AT₁R expression and lower renal AT₂R expression than their adult counterparts. Thus, depressor/pressor balance of the renal RAS is shifted towards the pressor RAS in reproductively senescent female mice. Collectively, the studies performed in this thesis demonstrate that the depressor RAS pathways play a protective role in the regulation of arterial pressure in adult females. Moreover, we demonstrate for the first time that these depressor RAS pathways wane with age in reproductively senescent females. This suggests that reduced expression and/or signalling of the depressor RAS pathways may contribute to the increase in arterial pressure in postmenopausal women. Therefore, targeting deficits in the depressor RAS pathways represents a novel therapeutic approach to the treatment of hypertension.