Alleviating Hypertension by Selectively Targeting Angiotensin Receptor-Expressing Vagal Sensory Neurons

Area of Science:

• Neuroscience
• Cardiovascular Physiology
• Molecular Biology

Background:

• Cardiovascular homeostasis relies on neural signals from arterial baroreceptors.
• The role of specific neurons expressing angiotensin type-1a receptors (NG^AT1aR) in baroreception remains unclear.

Purpose of the Study:

• To investigate whether nodose ganglia neurons expressing angiotensin type-1a receptors (NG^AT1aR) function as baroreceptors.
• To determine if NG^AT1aR differentially influence blood pressure in male and female mice.
• To elucidate the neuroanatomical and functional properties of NG^AT1aR.

Main Methods:

• Utilized Agtr1a-Cre mice and Cre-dependent AAVs for neuroanatomical tracing (tdTomato).
• Employed two-photon intravital imaging with GCaMP6s to monitor neuronal activity in response to blood pressure changes.
• Used optogenetics (channelrhodopsin-2) to stimulate NG^AT1aR and assess cardiovascular responses.
• Investigated responses in both normotensive and hypertensive (DOCA-salt, angiotensin II) mouse models.

Main Results:

• NG^AT1aR receive input from the aortic arch, project to the NTS, and express mechanosensitive channels Piezo1/2.
• NG^AT1aR firing increases with elevated blood pressure.
• Optical stimulation of NG^AT1aR elicits frequency-dependent decreases in blood pressure and heart rate.
• Hypertension models (DOCA-salt, angiotensin II) showed altered or delayed responses, suggesting baroreflex impairment.

Conclusions:

• NG^AT1aR function as baroreceptors, integrating vascular mechanosensation and angiotensin signaling.
• These neurons are critical for regulating blood pressure and heart rate.
• Dysfunctional NG^AT1aR signaling may contribute to hypertension, presenting potential therapeutic targets.