Angiotensin-(1-7) and Hypothalamic control of blood pressure

PROJECT SUMMARY
Obesity is a global epidemic that is associated with excessive central sympathetic outflow to cardiovascular
end organs to elevate blood pressure and predispose to hypertension. Accumulating evidence from our
laboratory suggests that deficiency of angiotensin-(1-7), a protective hormone of the renin-angiotensin system,
provides an important link connecting obesity with sympathetic overactivation and hypertension. Our published
observations, combined with preliminary data, support this concept by showing that high fat diet-induced obese
mice exhibit circulating angiotensin-(1-7) deficiency, and restoration of this hormone attenuates cardiovascular
sympathetic overactivity and hypertension in this model. Our preliminary data expand on these phenotypic
findings by providing evidence that angiotensin-(1-7) depressor effects require activation of neural circuits
originating in the arcuate nucleus of the hypothalamus (ARC). We show that both systemic and intra-ARC
angiotensin-(1-7) lowers blood pressure in mice, with effects prevented by deletion of angiotensin-(1-7) mas
receptors in the ARC. We further show that blood pressure lowering effects of angiotensin-(1-7) require
activation of specific subpopulations of ARC neurons that are likely proopiomelanocortin (POMC)-expressing,
as well as cyclic AMP second messenger systems. We propose that angiotensin-(1-7) selectively activates
POMC neurons that release the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). In support of
this, we show that: mas receptors are highly localized to GABAergic POMC neurons; and angiotensin-(1-7)
increases GABA synthesis enzymes in the ARC without altering POMC gene expression. Based on these data,
this proposal will test the central hypothesis that angiotensin-(1-7) activates mas receptors on GABAergic
POMC neurons in the ARC to reduce cardiovascular sympathetic outflow and lower blood pressure. Aim 1 will
determine if angiotensin-(1-7) selectively increases the excitability of GABAergic ARC POMC neurons using
transgenic mouse reporter lines combined with whole cell patch clamp electrophysiology methods. Aim 2 will
determine if angiotensin-(1-7) requires mas receptors in ARC POMC neurons to lower blood pressure via
GABA release mechanisms using a novel mas receptor conditional knockout mouse model we developed and
chemogenetic and pharmacological approaches. Aim 3 will determine if angiotensin-(1-7) decreases
sympathetic nerve traffic to cardiovascular organs using sophisticated in vivo isolated nerve recording
approaches. These studies will be conducted in male and female mice under control and high fat diet
conditions, to determine the impact of sex and obesity on angiotensin-(1-7) activation of this neural circuit.
Overall, this proposal will span the cellular to whole animal levels to provide new insight into angiotensin-(1-7)
effects on neural circuits controlling sympathetic outflow and blood pressure, and related cellular and
neurotransmitter mechanisms. Importantly, these studies have more long-term potential to determine if
targeting angiotensin-(1-7) represents a novel approach for the treatment of obesity-related hypertension.

Grant Number: 5R01HL156986-05
NIH Institute/Center: NIH
Principal Investigator: Amy Arnold