Homeostatic Signal Convergence in Vagal Baroreceptors

All organs, and most sensitively the brain, depend on consistent delivery of oxygen-rich blood. When blood flow is interrupted, organs (and consequently, sometimes organisms) die. Conversely, when blood flow to an organ is excessive, blood vessels can rupture, lungs can fill with fluid, and kidneys can scar. Because cardiovascular homeostasis is thus central to life, several neural, neurohormonal, and non-neural systems act to regulate variance in cardiovascular parameters.

A key homeostatic mechanism in the cardiovascular system is the baroreflex (Kumada et al., 1990). As blood pressure rises (or falls), the baroreflex opposes the perturbation with compensatory decreases (or increases) in heart rate and vascular tone. This negative feedback system is critical for stabilizing blood pressure. In its absence, blood pressure is markedly more variable. In addition, because the baroreflex is experimentally accessible and reliably recruits the principal effectors of cardiovascular control (sympathetic and parasympathetic efferents and hormonal secretion), it has become the dominant model for understanding the neurobiology of cardiovascular homeostasis.

Broadly, the cells and circuits subserving the baroreflex have been known for decades. Blood pressure is detected by baroreceptors, primary sensory neurons whose cell bodies reside in the nodose and petrosal ganglia of the vagus and glossopharyngeal nerves (Kumada et al., 1990). Baroreceptors have sensory endings in arterial walls, prominently in the carotid sinus and aortic arch, and they communicate a heartbeat-entrained, blood pressure-dependent signal to the nucleus of the solitary tract (NTS). Baro-recipient regions of the NTS send excitatory projections to preganglionic parasympathetic neurons of the nucleus ambiguus (which lower heart rate) and also indirectly inhibit the rostral ventral lateral medulla, a key driver of sympathetic vasoconstriction. This reflex arc through the medulla, in concert with important but lesser-studied supramedullary contributions, acts to ensure consistent organ perfusion.

In recent years, molecular dissection of the nodose and petrosal (NP) ganglia has revealed new features of the brain's ability to create rich sensory representations of the internal milieu, called interoception. Baroreceptor axons are bundled together with parasympathetic efferents and other sensory afferents that link virtually every internal organ to the brain. Classical experiments using lesion, stimulation, and recording of these mixed nerves (especially their terminal branches near sensory endings) generated foundational physiological insights—including, indeed, the very existence of the baroreflex (reviewed in Prescott and Liberles, 2022). Recently, however, molecular tools have enabled a finer scale characterization of the transcriptomic and marker-defined cell types, morphologies, and molecular details of the sensory neurons of interoception.

In the cardiovascular domain, a landmark discovery was that baroreceptors sense arterial pressure using a combination of the mechanosensitive ion channels PIEZO1 and PIEZO2 (Zeng et al., 2018). To probe the baroreflex, researchers often administer pharmacological agents like phenylephrine, an α-1-adrenergic agonist that induces vasoconstriction, blood pressure increases, and baroreflex-mediated compensatory decreases in vascular tone and heart rate. In animals lacking both Piezo1 and Piezo2 in NP ganglia, the baroreflex response to phenylephrine is abolished. Phenylephrine does not induce any change in heart rate in these animals. Similarly, when Piezo2-expressing cells are genetically ablated using diphtheria toxin, the baroreflex is abolished (Min et al., 2019). These loss-of-function experiments argue compellingly that Piezo2 expression defines a population of NP cells that includes all baroreceptors, of which a subset also express Piezo1. Consistent with these loss-of-function experiments, stimulation of Piezo2-expressing cells is sufficient to drive the baroreflex (Zeng et al., 2018; Min et al., 2019). These landmark studies thus revealed both the molecular mechanism of blood pressure transduction in baroreceptors and a key marker of baroreceptor neurons (Piezo2).

A recent paper in The Journal of Neuroscience (Baumer-Harrison et al., 2024) adds important new insights to this emerging story. Because angiotensin II is a key hormone involved in the regulation of blood pressure, osmolarity, and volume, the authors chose to focus on NP ganglion cells expressing the angiotensin II receptor, Agtr1a. Using a Cre-driver line to selectively label Agtr1a-expressing cells, they discovered that Agtr1a expression defines a subpopulation of NP ganglion cells, some of which have sensory endings in the aortic arch and send central projections to the NTS, consistent with the known anatomy of baroreceptors. Optical activation of channelrhodopsin-expressing Agtr1a-positive cells in NP ganglia produced a dose-dependent decrease in heart rate and blood pressure. Furthermore, Ca²⁺ imaging in Agtr1a NP ganglion cells revealed that these neurons are activated by phenylephrine-induced blood pressure increases. Agtr1a-expressing cells of the NP ganglion thus exhibit the hallmarks of baroreceptors.

This new finding that some baroreceptors express angiotensin II receptors is important in part because angiotensinergic signaling mechanisms are a key drug target in hypertension and heart failure, which together account for a large fraction of cardiovascular disease. Yet more interesting, because angiotensin II is part of a long signaling arc that begins with low blood flow and low sodium delivery to the kidney, the neurons identified in this study may form an early convergence point for blood pressure regulation by both slow, renally initiated signals and faster, baroreceptor-derived signals.

An important unanswered question is: what is the relationship between Piezo2-expressing and Agtr1a-expressing cells in NP ganglia? Either Piezo2 or Agtr1a expression, considered independently, defines a population of cells that includes baroreceptors. But neither marker is specific to baroreceptors—both Agtr1a and Piezo2 are expressed in NP ganglion cells with sensory endings in anatomical locations remote from the vascular system. While several landmark studies have performed single-cell RNA sequencing of NP ganglia (reviewed in Prescott and Liberles, 2022) and identified new transcriptomic cell types, separable transcriptomic types for baroreceptors have not yet been identified. To do so would likely require characterizing RNA expression in cells labeled retrogradely from the carotid sinus and/or aortic arch, combined with physiology experiments to distinguish baroreceptors from anatomically similar chemoreceptors. These are challenging experiments that have not yet been accomplished. Therefore, it is not yet possible to look for co-expression of Piezo2 and Agtr1a in single-cell transcriptomic data of identified baroreceptors. The study by Baumer-Harrison et al. (2024) makes an important contribution, however, by demonstrating that ∼30% of Agtr1a cells express Piezo2 and a similar proportion of Agtr1a cells express Piezo1. Because co-expression of Piezo1 and Piezo2 was not examined in the study, the extent to which Agtr1a cells express a single Piezo channel or both channels remains unclear. Based on earlier literature demonstrating the necessity of PIEZO1 and PIEZO2 channels and Piezo2-expressing cells in the baroreflex, it is presumably the subset of Agtr1a cells that also express Piezo2 that function as baroreceptors. This finding leads to several interesting questions for future research. Are Agtr1a-expressing cells also necessary for the baroreflex? In this case, does the intersection of Agtr1a and Piezo2 expression uniquely define baroreceptors? Alternatively, does Agtr1a expression define a subset of baroreceptors with additional or separable functions?

Another important question concerns the role of angiotensin II signaling in baroreceptors. Angiotensin II links renal detection of low blood flow and low salt delivery to compensatory neural and hormonal responses. In the brain, angiotensin II receptors are present throughout the regions of the lamina terminalis including the circumventricular subfornical organ (SFO) and organum vasculosum of the vascular tract (OVLT), both of which reside partly outside the blood–brain barrier and maintain access to circulating angiotensin II. Angiotensin II facilitates activity in the OVLT and SFO (Zimmerman et al., 2016; Kinsman et al., 2020), and activity in these cells, through their projections to downstream median preoptic area, drives water-seeking behavior, the negative affective valence of thirst, and increases in blood pressure (Allen et al., 2017; Leib et al., 2017). This organization provides a mean by which a low volume or low salt physiological state, as detected by the kidney and signaled by angiotensin II, can affect brain circuits that direct behavior and autonomic outputs that oppose a physiological disturbance.

In baroreceptors, however, angiotensin signaling appears to be more complicated than in the lamina terminalis. Circulating angiotensin II tends to increase blood pressure via direct effects on the vasculature, neurally mediated increases in vasoconstriction, and stimulation of secretion of aldosterone and vasopressin. The Agtr1a receptor is a G-protein-coupled receptor, coupled to G_q proteins, which are generally excitatory. This creates a bit of a paradox as baroreceptor activity tends to decrease (rather than increase) blood pressure. One possible resolution is that angiotensin II inhibits (rather than facilitates) the activity of baroreceptors. This inhibition, should it occur, might play a role in classical observations of blunted baroreflex sensitivity or baroreflex “set point” increases reported with angiotensin II administration (Tan et al., 2007). Alternatively, angiotensin II may modulate baroreceptor signaling in some other way, yet to be elucidated. There is much more to be discovered. But the study by Baumer-Harrison et al. (2024) is an exciting advance toward an understanding of the complex neural and hormonal signaling mechanisms linking the brain and numerous organ systems in the integrated control of blood pressure, osmolarity, and volume.