Alleviating hypertension by selectively targeting angiotensin receptor expressing vagal sensory neurons

Abstract

Cardiovascular homeostasis is maintained, in part, by neural signals arising from arterial baroreceptors that apprise the brain of blood volume and pressure. Here, we test whether neurons within the nodose ganglia that express angiotensin type-1a receptors (referred to as NG AT1aR ) serve as baroreceptors that differentially influence blood pressure (BP) in male and female mice. Using Agtr1a -Cre mice and Cre-dependent AAVs to direct tdTomato to NG AT1aR , neuroanatomical studies revealed that NG AT1aR receive input from the aortic arch, project to the caudal nucleus of the solitary tract (NTS), and synthesize mechanosensitive ion channels, Piezo-1/-2 . To evaluate the functionality of NG AT1aR , we directed the fluorescent calcium indicator (GCaMP6s) or the light-sensitive channelrhodopsin-2 (ChR2) to Agtr1a -containing neurons. Two-photon intravital imaging in Agtr1a -GCaMP6s mice revealed that NG AT1aR couple their firing to elevated BP, induced by phenylephrine (i.v.). Furthermore, optical excitation of NG AT1aR at their soma or axon terminals within the caudal NTS of Agtr1a -ChR2 mice elicited robust frequency-dependent decreases in BP and heart rate, indicating that NG AT1aR are sufficient to elicit appropriate compensatory responses to vascular mechanosensation. Optical excitation also elicited hypotensive and bradycardic responses in ChR2-expressing mice that were subjected to deoxycorticosterone acetate (DOCA)-salt hypertension; however, the duration of these effects was altered, suggestive of hypertension-induced impairment of the baroreflex. Similarly, increased GCaMP6s fluorescence observed after administration of phenylephrine was delayed in mice subjected to DOCA-salt or chronic delivery of angiotensin-II. Collectively, these results reveal the structure and function of NG AT1aR and suggest that such neurons may be exploited to discern and relieve hypertension. Significance Statement Hypertension is a major risk factor for cardiovascular disease and stroke, the 1 st and 5 th leading causes of death in the U.S. Half of the adult population is afflicted with hypertension, with many not having their condition under control with current treatment options. Thus, there is a need to discover novel targets and develop new antihypertensive therapeutics. Here, we characterize the structure and function of vagal sensory neurons that express the angiotensin-II type 1a receptor (AT1aR) and provide evidence that these neurons are involved in blood pressure control. The implication is that AT1aR serve as a phenotypic marker for a subset of vagal baroreceptive neurons that may serve as a novel route to understand and alleviate hypertension.

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