Alleviating hypertension by selectively targeting angiotensin receptor expressing vagal sensory neurons

作者：Caitlin Baumer-Harrison, Khalid Elsaafien, Dominique N. Johnson, Jesus D. Peñaloza Aponte, Alan de Araujo, Sagar Y. Patel, Erin B. Bruce, Scott W. Harden, Charles J. Frazier, Karen A. Scott, Guillaume de Lartigue, Eric G. Krause, Annette D. de Kloet · 发表于：Journal of Neuroscience · 年份：2024 · DOI：10.1523/jneurosci.1154-23.2023 · 被引用次数：13 · 研究领域：Renin-Angiotensin System Studies、Circadian rhythm and melatonin、Receptor Mechanisms and Signaling

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 NGAT1aR) serve as baroreceptors that differentially influence blood pressure (BP) in male and female mice. UsingAgtr1a-Cre mice and Cre-dependent AAVs to direct tdTomato to NGAT1aR, neuroanatomical studies revealed that NGAT1aRreceive 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 NGAT1aR, we directed the fluorescent calcium indicator (GCaMP6s) or the light-sensitive channelrhodopsin-2 (ChR2) toAgtr1a-containing neurons. Two-photon intravital imaging inAgtr1a-GCaMP6s mice revealed that NGAT1aRcouple their firing to elevated BP, induced by phenylephrine (i.v.). Furthermore, optical excitation of NGAT1aRat their soma or axon terminals within the caudal NTS ofAgtr1a-ChR2 mice elicited robust frequency-dependent decreases in BP and heart rate, indicating that NGAT1aRare 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...