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Sex differences in cardiovascular actions of the renin-angiotensin system.

ABSTRACT: Cardiovascular disease (CVD) remains a worldwide public health concern despite decades of research and the availability of numerous targeted therapies. While the intrinsic physiological mechanisms regulating cardiovascular function are similar between males and females, marked sex differences have been established in terms of CVD onset, pathophysiology, manifestation, susceptibility, prevalence, treatment responses and outcomes in animal models and clinical populations. Premenopausal females are generally protected from CVD in comparison to men of similar age, with females tending to develop cardiovascular complications later in life following menopause. Emerging evidence suggests this cardioprotection in females is, in part, attributed to sex differences in hormonal regulators, such as the renin-angiotensin system (RAS). To date, research has largely focused on canonical RAS pathways and shown that premenopausal females are protected from cardiovascular derangements produced by activation of angiotensin II pathways. More recently, a vasodilatory arm of the RAS has emerged that is characterized by angiotensin-(1-7) [(Ang-(1-7)], angiotensin-converting enzyme 2 and Mas receptors. Emerging studies provide evidence for a shift towards these cardioprotective Ang-(1-7) pathways in females, with effects modulated by interactions with estrogen. Despite well-established sex differences, female comparison studies on cardiovascular outcomes are lacking at both the preclinical and clinical levels. Furthermore, there are no specific guidelines in place for the treatment of cardiovascular disease in men versus women, including therapies targeting the RAS. This review summarizes current knowledge on sex differences in the cardiovascular actions of the RAS, focusing on interactions with gonadal hormones, emerging data for protective Ang-(1-7) pathways and potential clinical implications for established and novel therapies.

SUBMITTER: Medina D

PROVIDER: S-EPMC7572792 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: Genetically hypertensive BPH/2J mice are recognized as a neurogenic model of hypertension, primarily based on sympathetic overactivity and greater neuronal activity in cardiovascular regulatory brain regions. Greater activity of the central renin angiotensin system (RAS) and reactive oxygen species (ROS) reportedly contribute to other models of hypertension. Importantly the peripheral RAS contributes to the hypertension in BPH/2J mice, predominantly during the dark period of the 24 h light cycle. The aim of the present study was to determine whether central AT1 receptor stimulation and the associated ROS signaling contribute to hypertension in BPH/2J mice in a circadian dependent manner. Methods: Blood pressure (BP) was measured in BPH/2J and normotensive BPN/3J mice (n = 7-8) via pre-implanted telemetry devices. Acute intracerebroventricular (ICV) microinjections of AT1 receptor antagonist, candesartan, and the superoxide dismutase (SOD) mimetic, tempol, were administered during the dark and light period of the 24 h light cycle via a pre-implanted ICV guide cannula. In separate mice, the BP effect of ICV infusion of the AT1 receptor antagonist losartan for 7 days was compared with subcutaneous infusion to determine the contribution of the central RAS to hypertension in BPH/2J mice. Results: Candesartan administered ICV during the dark period induced depressor responses which were 40% smaller in BPH/2J than BPN/3J mice (Pstrain < 0.05), suggesting AT1 receptor stimulation may contribute less to BP maintenance in BPH/2J mice. During the light period candesartan had minimal effect on BP in either strain. ICV tempol had comparable effects on BP between strains during the light and dark period (Pstrain > 0.08), suggesting ROS signaling is also not contributing to the hypertension in BPH/2J mice. Chronic ICV administration of losartan (22 nmol/h) had minimal effect on BPN/3J mice. By contrast in BPH/2J mice, both ICV and subcutaneously administered losartan induced similar hypotensive responses (-12.1 ± 1.8 vs. -14.7 ± 1.8 mmHg, Proute = 0.31). Conclusion: While central effects of peripheral losartan cannot be excluded, we suggest the hypotensive effect of chronic ICV losartan was likely peripherally mediated. Thus, based on both acute and chronic AT1 receptor inhibition and acute ROS inhibition, our findings suggest that greater activation of central AT1 receptors or ROS are unlikely to be mediating the hypertension in BPH/2J mice.

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Sex differences in cardiovascular actions of the renin-angiotensin system.

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