Angiotensin-(1-7) and Central Control of Cardiometabolic Outcomes: Implications for Obesity Hypertension

Abstract

Hypertension is a leading independent risk factor for the development of cardiovascular disease, the leading cause of death globally. Importantly, the prevalence of hypertension is positively correlated with obesity, with obesity-related hypertension being difficult to treat due to a lack of current guidelines in this population as well as limited efficacy and adverse off-target effects of currently available antihypertensive therapeutics. This highlights the need to better understand the mechanisms linking hypertension with obesity to develop optimal therapeutic approaches. In this regard, the renin-angiotensin system, which is dysregulated in both hypertension and obesity, is a prime therapeutic target. While research and therapies have typically focused on the deleterious angiotensin II axis of the renin-angiotensin system, emerging evidence shows that targeting the protective angiotensin-(1-7) axis also improves cardiovascular and metabolic functions in animal models of obesity hypertension. While the precise mechanisms involved remain under investigation, in addition to peripheral actions, evidence exists to support a role for the central nervous system in the beneficial cardiometabolic effects of angiotensin-(1-7). This review will highlight emerging translational studies exploring the cardiovascular and metabolic regulatory actions of angiotensin-(1-7), with an emphasis on its central actions in brain regions including the brainstem and hypothalamus. An improved understanding of the central mechanisms engaged by angiotensin-(1-7) to regulate cardiovascular and metabolic functions may provide insight into the potential of targeting this hormone as a novel therapeutic approach for obesity-related hypertension.

Keywords: blood pressure; brain; metabolism; obesity; renin–angiotensin system.

Figure 1

RAS hormones elicit differential cardiometabolic effects by binding to specific angiotensin receptors. AT1R: angiotensin II type 1 receptor; AT2R: angiotensin II type 2 receptor; MasR: angiotensin-(1-7) Mas receptor; MrgD: Mas-related G protein-coupled receptor; SNS: sympathetic nervous system; PSNS: parasympathetic nervous system; BP: blood pressure; BRS: baroreflex sensitivity; NO: nitric oxide. Created in BioRender. Arnold, A. (2024) https://BioRender.com/e19f735 (accessed on 11 December 2024).

Figure 2

Cross sections of cardiometabolic nuclei in the hypothalamus and brainstem of the mouse brain and their major physiological functions. PVN: the paraventricular nucleus of the hypothalamus; ARC: the arcuate nucleus of the hypothalamus; NTS: the nucleus tractus solitarius; RVLM: the rostral ventrolateral medulla; CVLM: the caudal ventrolateral medulla. The areas highlighted in red represent the circumventricular organs. OVLT: the organum vasculosum of the lamina terminalis; ME: the median eminence; SFO: the subfornical organ; AP: the area postrema. Dotted lines represent the approximate location of the cross sections displayed. Created in BioRender. Arnold, A. (2024) https://BioRender.com/o23u712 (accessed on 13 November 2024).