Download Role of neurons and glia in the CNS actions of the renin

Am J Physiol Regul Integr Comp Physiol 309: R444 –R458, 2015.
First published July 8, 2015; doi:10.1152/ajpregu.00078.2015.
Review
Role of neurons and glia in the CNS actions of the renin-angiotensin system
in cardiovascular control
Annette D. de Kloet,1 Meng Liu,1 Vermalí Rodríguez,1 Eric G. Krause,2 and Colin Sumners1
1
Department of Physiology and Functional Genomics, and McKnight Brain Institute, University of Florida College of
Medicine, Gainesville, Florida; and 2Department of Pharmacodynamics, University of Florida College of Pharmacy,
Gainesville, Florida
Submitted 27 February 2015; accepted in final form 15 June 2015
neurogenic hypertension; astrocyte; microglia; renin; angiotensin II
system are the predominant
causes of mortality in the United States (128), and it is
imperative that new and innovative strategies to combat these
pathologies are developed. This can only be achieved with a
thorough understanding of the systems that regulate cardiovascular control under normal and pathological conditions. The
central nervous system (CNS) is crucial to maintaining cardiovascular homeostasis. Dysregulation of the neural systems
controlling cardiovascular function can lead to chronic sympathoexcitation and so-called “neurogenic hypertension”, a key
contributor to the development of cardiovascular disease (72,
128). Despite the known risks of chronically elevated blood
pressure, therapeutics that effectively and consistently normalize high blood pressure in hypertensive patients remain elusive;
this is particularly so for neurogenic hypertension. As a consequence, many hypertensive patients exhibit resistance to
current antihypertensive medications (128, 159). Two important aspects of the CNS control of blood pressure that are
DISEASES OF THE CARDIOVASCULAR
Address for reprint requests and other correspondence: C. Sumners, Dept. of
Physiology and Functional Genomics, Univ. of Florida, 1600 SW Archer Rd.,
Gainesville, FL 32610-0274 (e-mail: [email protected]).
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promising areas of focus for the enhancement of therapeutic
interventions are 1) the newly recognized complexity of the
influence of the renin-angiotensin system (RAS) over cardiovascular control (37, 44, 98, 111, 164) and 2) the impact of
neuronal-glial interactions within cardiovascular control centers of the brain on these processes (19, 39, 104, 167, 168, 170,
179). The RAS and neuronal-glial interactions become altered
in disease states and are intimately interrelated (39, 41, 192,
194). That is, the RAS influences neuronal-glial interactions,
while communication between glial and neural cells impacts
brain RAS signaling (39, 41, 168, 169).
To further illustrate the interactions between the RAS and
neuron-glia communication, glial cells are often recognized as
the innate immune cells of the brain (53, 59, 99, 133), and
ANG II has long been recognized to exert immunomodulatory
effects within various tissues by activating its type-1 receptor
(AT1R) (11, 155). Additionally, other, more recently identified,
components of the RAS, such as (pro)renin and its (pro)renin
receptor (PRR), are thought to impact the neural control of
cardiovascular function, potentially by impacting neuron-glial
interactions and inflammatory pathways within the brain (110,
111, 131, 132, 164).
0363-6119/15 Copyright © 2015 the American Physiological Society
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de Kloet AD, Liu M, Rodríguez V, Krause EG, Sumners C. Role of neurons
and glia in the CNS actions of the renin-angiotensin system in cardiovascular
control. Am J Physiol Regul Integr Comp Physiol 309: R444 –R458, 2015. First
published July 8, 2015; doi:10.1152/ajpregu.00078.2015.—Despite tremendous
research efforts, hypertension remains an epidemic health concern, leading often to
the development of cardiovascular disease. It is well established that in many
instances, the brain plays an important role in the onset and progression of
hypertension via activation of the sympathetic nervous system. Further, the activity
of the renin-angiotensin system (RAS) and of glial cell-mediated proinflammatory
processes have independently been linked to this neural control and are, as a
consequence, both attractive targets for the development of antihypertensive therapeutics. Although it is clear that the predominant effector peptide of the RAS,
ANG II, activates its type-1 receptor on neurons to mediate some of its hypertensive
actions, additional nuances of this brain RAS control of blood pressure are
constantly being uncovered. One of these complexities is that the RAS is now
thought to impact cardiovascular control, in part, via facilitating a glial celldependent proinflammatory milieu within cardiovascular control centers. Another
complexity is that the newly characterized antihypertensive limbs of the RAS are
now recognized to, in many cases, antagonize the prohypertensive ANG II type 1
receptor (AT1R)-mediated effects. That being said, the mechanism by which the
RAS, glia, and neurons interact to regulate blood pressure is an active area of
ongoing research. Here, we review the current understanding of these interactions
and present a hypothetical model of how these exchanges may ultimately regulate
cardiovascular function.
Review
ROLE OF CNS RAS, NEURONS, AND GLIA IN CARDIOVASCULAR CONTROL
Cellular Localization of the Renin-Angiotensin System
Components Within the Brain
Countless efforts have been made to provide a thorough
characterization of the cellular localization of components of
the RAS within the brain. These efforts have been somewhat
complicated by the unreliability of angiotensin receptor antibodies (9, 73, 79) and the poor cellular resolution of angiotensin receptor autoradiography techniques. That being said, decades of research have led to a tremendous literature base that
collectively localizes all of the integral components of the RAS
to the various cell populations within the brain (36, 37, 42, 62,
83, 86, 105, 123, 151, 157, 180).
Localization of components for ANG II synthesis. The inability of circulating ANG II to effectively cross the bloodbrain barrier (BBB) under normal, healthy conditions coupled
with the dense localization of ANG II receptors to brain
structures that are protected by the BBB has led to the prediction that ANG II can be synthesized within the brain to act in
an autocrine or paracrine fashion at its CNS receptors. There
are studies that have suggested that the production of ANG II
occurs within the neurons themselves and that ANG II is
generated intracellularly and on demand to act as a peptide
neurotransmitter within neural circuits that regulate cardiovascular function (7, 68, 112). However, additional intricacies
involved in CNS ANG II synthesis may be inferred by the
localization of the components required for its production to
multiple cell types within the brain, rather than exclusively to
one cellular phenotype.
The ANG II precursor, angiotensinogen, is densely expressed within the CNS, and, in particular, within astrocytes
(85, 151, 162, 180). Renin, which converts angiotensinogen to
ANG I, is also localized to neurons and astrocytes; however,
the low expression of this enzyme within the CNS has led to
reservations in regard to its functional significance (83, 86, 87,
114, 142). On the other hand, the PRR, which binds (pro)renin,
thereby sequestering and rendering it active to convert angiotensinogen to ANG I, is highly expressed in the brain, perhaps
providing a mechanism by which ANG II may be synthesized
within the CNS (37, 131, 132). Along these lines, this receptor
is thought to be involved in the autocrine/paracrine actions of
the RAS within several specific tissues, including the brain (37,
131, 132). Furthermore, PRR is associated with intracellular
signaling cascades that act independently of ANG II receptor
signaling to facilitate the development of neurogenic hypertension (37, 164). PRRs are particularly abundant on neurons
(111, 164, 188) and are also localized to microglia (169) and
astrocytes (152). An additional mechanism by which ANG II
may be generated within the brain, despite the low levels of
renin observed within this tissue, involves another peptide
derived from angiotensinogen, proangiotensin-12, or ANG
1–12 (129). This peptide is also present in the brain and may
allow for ANG II generation independent of renin (129).
Angiotensin-converting enzyme (ACE) is the next step in
the generation of ANG II, and this enzyme is also present in the
brain (36, 62, 157), with a particular abundance in the choroid
plexus and in the capillary endothelial cells (5, 23) and also to
a lesser extent in neurons within a few regions that are involved
in the neural regulation of blood pressure, such as the subfornical organ (SFO) and paraventricular nucleus of the hypothalamus (PVN) (156, 182). Collectively, the localization of the
RAS components required for the synthesis of ANG II within
diverse cell types of the brain implies that a network of
neuronal-glial interactions may be required for the synthesis of
ANG II within the brain. Once ANG II is synthesized within
the brain, it likely activates its AT1R and AT2R in BBBprotected nuclei to influence cardiovascular function and hydromineral balance.
Cellular localization of receptors mediating ANG II action.
ANG II binds to either the AT1R or the AT2R to exert its
physiological actions, and these receptors are found within the
CNS (42, 67, 77, 92–94, 105, 124, 195). Whereas humans
contain only AT1R and AT2R, the AT1R subtype within
rodents can be further subdivided into the angiotensin type 1a
receptor (AT1aR) and type 1b receptor (AT1bR), whose genes
are present on separate chromosomes but are highly homologous (119, 160). Within the brain of rodents, AT1R is primarily
present in its AT1aR form; however, in some cases, AT1bR has
been detected in the brain, and it is also abundant in the
anterior pituitary and adrenal cortex (27, 95, 105).
In rodents, AT1Rs (primarily AT1aR) are abundant in regions that are traditionally known to regulate blood pressure
and hydromineral balance, including the PVN and SFO (105),
while AT2R are densely expressed in a number limbic and
thalamic regions that indirectly regulate cardiovascular function, as well as some regions that play a more direct role in
cardiovascular homeostasis, such as the nucleus of the solitary
tract (NTS) (42, 77, 92, 93). Despite the seeming consensus
regarding the localization of these receptors to specific brain
nuclei, the cellular localization of the angiotensin receptors
within the brain has been a matter of debate. In contrast to
immunohistochemistry (IHC) and in vitro studies that have
localized AT1R and AT2R to non-neuronal cells in the brain
(108, 127, 207), genetic mouse models and advances in in situ
hybridization provide evidence that, at least under normal
conditions, these receptor subtypes are predominantly neuronal
and are absent from glia (33, 42, 67). In support of a predominantly neuronal localization of AT1aR within a cardiovascular
control center, Fig. 1 depicts dual in situ hybridization and
immunohistochemistry studies localizing this receptor to HuC/
D-positive neurons in normotensive rat PVN, but not to Iba1-positive microglia or GFAP-positive astrocytes. As can be
observed in this figure, although microglia and astrocytes
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Here, we review the role of neural and glial cells in the brain
regulation of cardiovascular function by the RAS. To accomplish this, we first provide a brief overview of what is known
regarding the localization of the RAS components to specific
cell types within the brain. We then review the well-characterized impact of ANG II activation of neuronal AT1R in the
brain regulation of cardiovascular function. Next, the role of
communication between neurons and glia in the control of
cardiovascular function is discussed, as is the impact that ANG
II has on these interactions. The complementary influence of
PRR signaling and the counterregulatory impact of other components of the RAS [e.g., angiotensin-converting enzyme 2,
and angiotensin type 2 receptors (AT2R)] on these processes
are also considered. Last, we present a hypothetical model of
how the RAS may impact neuronal-glial interactions during
cardiovascular pathology and how elucidating these interactions may lead to the development of novel antihypertensive
therapeutics.
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ROLE OF CNS RAS, NEURONS, AND GLIA IN CARDIOVASCULAR CONTROL
themselves lack AT1aR expression, they are situated in close
proximity to AT1aR-containing neurons. These cells are, therefore, positioned to interact intimately with one another.
Importantly these highly specific and sensitive in situ hybridization and genetic techniques for the localization of ANG
II receptors have not yet been extended to models of cardiovascular pathophysiology, in which it is possible that AT1R
and/or AT2R may become expressed on the non-neuronal cell
types of the brain. However, it is probable that these technological advancements may be utilized in future studies to
definitively ascertain the impact of cardiovascular pathology
on the cellular localization of ANG II receptors in the brain.
Along these lines, there are a number of previous in vitro and
some in vivo studies that have suggested a role for angiotensin
receptors on non-neuronal brain cells in the development and
progression of hypertension, and these studies will be discussed in subsequent sections.
Cellular localization of the ANG 1–7 receptor, Mas. Other
nontraditional components of the RAS, such as the ANG 1–7
receptor, Mas, are thought to counter-regulate ANG II’s actions at its type-1 receptor and are detected within the brain
(75, 91, 212). Like the AT1R and AT2R, the Mas is a G
protein-coupled receptor that is found in various areas of the
brain, including the hippocampus, amygdala, forebrain, piriform cortex, olfactory bulb, thalamus, and portions of the
hypothalamus (25, 60, 125, 212). Although these previous
studies revealed that the Mas was primarily localized to neurons within these regions (60), others have observed Mas
localization to glial cells as well (150), implying that this axis
may directly and/or indirectly impact numerous cell types in
the brain to ultimately influence physiology.
Renin-Angiotensin System Actions Mediated via Neurons to
Regulate Cardiovascular Function
Because of the overwhelming acceptance that receptors for
RAS-mediated actions are localized to neurons, much research
has focused on the effects of their activation on the neuronal
regulation of cardiovascular function, and these neuronal actions have been extensively reviewed elsewhere (54, 58, 135,
141) and will, therefore, only briefly be discussed here. Importantly, and as described above, the prohypertensive AT1R and
PRR and the antihypertensive AT2R and Mas are localized to
neurons within brain regions both directly and indirectly involved in cardiovascular function. These regions include those
that are protected by the BBB (e.g., the NTS), as well as those
that are termed circumventricular organs (CVOs), which serve
as an interface between the systemic circulation and the brain.
The endocrine RAS is traditionally known to impact the
neural control of cardiovascular function via the activation of
AT1R in CVOs, such as the SFO (54 –56, 101, 136). These
CVO neurons then, in turn, send projections to and influence
the activity of numerous cardiovascular control centers that are
generally protected by the BBB, including the PVN (55, 101).
Upon activation of these CVO projections, the release of
traditional neurotransmitters (e.g., glutamate) from their nerve
terminals and onto neurons situated in downstream cardiovascular control nuclei is modulated, and sympathetic outflow and
blood pressure become elevated (161, 190). That being said,
many of these downstream brain nuclei also densely express
AT1R. As discussed in detail in Localization of components for
ANG II synthesis, it is recognized that the RAS acts as an
autocrine or paracrine system within a number of tissues,
including the brain (37, 105, 123), where it has been speculated
that brain-derived ANG II serves as a neurotransmitter within
circuits that regulate cardiovascular function (7, 112). Although, as described in detail above, the mechanism by which
ANG II would be synthesized within the brain and then
released from nerve terminals is a topic of ongoing research,
the putative ANG II neurotransmitter action is an intriguing
method by which BBB-protected AT1R may impact physiology, and it likely involves coordination among numerous cell
types in the brain.
Another mode by which ANG II has been proposed to
activate AT1R on neurons within cardiovascular control centers that are normally protected by the BBB is via passive
transport of circulating ANG II across a compromised (leaky)
BBB. To this point, there are various pathological conditions
that are accompanied by increased BBB permeability (16, 78,
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Fig. 1. AT1R localizes to neurons but not
astrocytes and microglia in the paraventricular nucleus (PVN). Representative images
through the PVN of normotensive SpragueDawley rats depicting AT1aR mRNA as
punctate green dots (in situ hybridization via
RNAscope) combined with dual-label immunohistochemistry for the neuronal marker
HuC/D, shown in red, and either the microglial marker Iba-1 (A–C) or the astrocytic
marker GFAP (D–F), both shown in magenta. Combined in situ hybridization and
immunohistochemistry were conducted as
described in detail in de Kloet et al. (42).
Scale ⫽ 10 ␮m.
Review
ROLE OF CNS RAS, NEURONS, AND GLIA IN CARDIOVASCULAR CONTROL
AT1R on RVLM-projecting PVN neurons to cause their depolarization (31) and 2) presynaptic disinhibition of preautonomic neurons via the activation of AT1R on GABAergic
nerve terminals that contact them (106, 107). Although, there is
some evidence to support both of these mechanisms, the
above-mentioned impediments to definitively localizing AT1R
to specific neuronal phenotypes have cast uncertainty upon
these propositions, as it is not entirely clear from anatomical
studies that the AT1R are localized to the correct neuronal
phenotypes to substantiate the involvement of these mechanisms. Further, it is also unclear as to whether these ANG II
actions are direct neuronal effects or are mediated via actions
of ANG II at other cell elements. That said, whether one or
both of the above-described mechanisms is, indeed, at play can
perhaps be definitively ascertained by the utilization of advanced genetic techniques, such as optogenetics and AT1R
reporter mice. Regardless, the end result of either of these
proposed mechanisms of ANG II actions within the PVN
would be an excitation of the preautonomic PVN neurons and
subsequent increase in blood pressure via projections onto
neurons of the RVLM and the intermediolateral cell column of
the spinal cord, and the available literature is supportive of an
excitatory role for AT1R activation on preautonomic neurons
(32, 35, 148, 163, 185).
Another important point is that the central RAS has been
implicated in the regulation of the magnocellular AVP system,
which likely also contributes to ANG II’s hypertensive effects
(115, 199, 213). Elevations in brain ANG II (or ANG III) lead
to activation of AVP neurons causing a rise in systemic AVP
levels that can be attenuated by administration of AT1R blockers either via the intracerebroventricular route or specifically
within magnocellular neuron-containing areas of the brain
(199, 213, 214). Further, several recent studies have indicated
that AVP may play an important role in RAS-dependent
hypertension. For example, the hypertension observed in mice
with transgenic activation of the brain RAS is AVP-dependent
(115). On the basis of data from BAC transgenic reporter mice,
it is unlikely that magnocellular neurons of the PVN (or
supraoptic nucleus) contain AT1R or AT2R (42, 67), and the
impact of ANG II on AVP secretion may be mediated by ANG
II receptor-positive neural connections arising from upstream
brain nuclei, such as the organum vasculosum of the lamina
terminalis or SFO (57, 193). Alternatively, it may also involve
non-neuronal cell types in the brain, and this notion will be
discussed in the subsequent sections. While these stimulatory
effects of ANG II on AVP secretion are likely mediated by the
AT1R (34, 199, 213), several lines of evidence support the
notion that activation of AT2R acts in opposition to these
hypertensive and AVP secretion stimulatory effects. For example, whole body genetic deletion or pharmacological blockade of AT2R (using PD123,219) in mice leads to increased
pressor responses to centrally administered ANG II. These
experimental manipulations also augment ANG II-induced
AVP release, reflected by an increase of plasma AVP levels
(80, 113) and decreased pituitary AVP content (118). That
being said, the therapeutic utility of AT2R agonists has only
recently begun to be evaluated in this regard.
The projections from the preautonomic portion of the PVN
to the hindbrain and spinal cord are generally glutamatergic,
and the release of glutamate from their synapses onto RVLM
neurons and preganglionic neurons in the intermediolateral cell
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122, 126), and it is possible that regions that are highly
vascularized, such as the PVN (174, 186), are particularly
susceptible to such a mechanism by which circulating ANG II
can access CNS receptors. In support of this notion, hypertension causes an ANG II-dependent increase in BBB permeability that then leads to the facilitated access of endocrine ANG II
to brain regions typically considered to be protected from
circulating factors (16). The interpretation is that there exists
an ANG II-contingent feed-forward mechanism potentiating
hypertensive actions by facilitating the access of ANG II to
cardiovascular control centers of the brain.
In any event, regardless of the origin of ANG II within the
brain, once levels of this peptide become elevated within
cardiovascular control centers and neuronal AT1R are activated, the outcome is in many instances an increase in sympathetic outflow and blood pressure. As a consequence, neuronal ANG II/AT1R actions are by and large thought to
facilitate neurogenic hypertension; granted, there is also evidence for ANG II/AT1R-dependent antihypertensive mechanisms within distinct brain nuclei such as the NTS (165) and
the caudal ventrolateral medulla (3). Further, many currently
prescribed ANG II receptor blockers cross the blood-brain
barrier and are thought to exert some of their antihypertensive
actions via the blockade of AT1R within the brain (18).
In regard to the neural circuitry of RAS-mediated cardiovascular actions, the PVN is one brain region containing
AT1Rs that are thought to facilitate neurogenic hypertension.
Neurons of the PVN can be divided into a number of functionally distinct subgroups based on their anatomical location
and neurochemical phenotype. Parvocellular PVN neurons,
many of which express AT1R (105), are classified as neurosecretory or preautonomic. The neurosecretory neurons project to
the median eminence and, upon stimulation, release factors
such as corticotropin-releasing hormone and thyrotropin-releasing hormone, which are integral components of the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitarythyroid axis, respectively. Preautonomic neurons influence
cardiovascular function by controlling sympathetic nervous
system activity via projections to the hindbrain [i.e., rostral
ventrolateral medulla (RVLM)] and spinal cord (31, 35, 196).
Magnocellular PVN neurons express vasopressin (AVP) or
oxytocin (187), and their activation results in the release of
AVP and oxytocin from the posterior pituitary and into the
circulation. Although the specific predominating roles for the
subgroups of neurons within the PVN are established, there is
some overlap and crosstalk between the subtypes of neurons of
the PVN. For example, preautonomic neurons can also express
markers that are specific to the other subregions of the PVN,
such as AVP. As a consequence, AVP neurons in the PVN may
impact blood pressure via effects on sympathetic outflow, as
well as their effects on AVP secretion. Moreover, there is a
growing body of evidence that indicates that various cell types
of the PVN communicate with one another via the dendritic
release of neuropeptides (51, 117, 172, 178). This phenomenon
allows for the effective integration and coordination of responses that are mediated by the PVN, and this area is reviewed in detail elsewhere (117, 178).
In regard to ANG II’s actions at preautonomic neurons of the
PVN, two potential mechanisms have been proposed for the
neuronal AT1R-mediated excitation of these neurons and consequent increases blood pressure: 1) ANG II stimulation of
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ROLE OF CNS RAS, NEURONS, AND GLIA IN CARDIOVASCULAR CONTROL
tensive actions have been postulated to be mediated by the
RVLM (65) and the NTS (17), among other brain areas
containing AT2R (42). Despite these lines of evidence, suggesting that AT2R and Mas-mediated mechanisms are antihypertensive, there are also studies that have revealed that ANG
1–7 administered into specific brain regions (e.g., the RVLM
or PVN) enhances cardiac sympathetic afferent reflex and
increases sympathetic outflow and blood pressure via Mas
activation (76, 109, 171).
Important questions are whether these countering effects of
AT2R and Mas over AT1R-mediated cardiovascular effects are
physiologically relevant, and under what physiological conditions might they occur. These questions are relevant because,
thus far, actions of AT2R and Mas have been uncovered under
pharmacological conditions. With regard to AT2R, it is known
that AT1R and AT2R are present at different levels of expression within various cardiovascular control centers. It is generally accepted that AT1R are more abundant than AT2R within
many of the cardiovascular control centers of the brain, and,
therefore, AT1R actions, in general, are thought to predominate. Nonetheless, AT2R actions are potentially dampening
these AT1R-mediated responses, such that if AT2R is blocked
pharmacologically or deleted genetically, AT1R actions are
often augmented (21, 84, 113). It is also important to note that
although these receptors are present within the same brain
nuclei, they are primarily localized to separate cells within
these sites (42). Thus, antagonistic actions of these receptors
within or near cardiovascular control centers are likely opposite or offsetting, rather than mediated through the same
neuron. Although brain AT1R and AT2R may have opposite
effects on cardiovascular control and there is anatomical evidence that shows they are found in close proximity to each
other, the physiological conditions that might precipitate predominance of one receptor subtype over the other, or increased
expression of one versus the other, are not established. Nonetheless, we feel that the AT2R does, indeed, play a physiological role in countering AT1R effects. Perhaps the ratio of AT1R
to AT2R is important in determining the extent of ANG II’s
hypertensive actions. Further, we hypothesize that AT2R can
be exploited pharmacologically to also counter AT1R-mediated
hypertension.
It is clear from the reviewed studies, as well as numerous
other reports, that the RAS can exert powerful cardiovascular
effects via direct actions on neurons. On the other hand,
AT1R-neuronal-glial interactions are an emerging area of interest, as is the impact of PRR activation and the counterregulatory AT2R and ACE2/ANG 1–7/Mas axis on neuronalglial communications, and consequently, on cardiovascular
function. These concepts are discussed in the subsequent sections.
Neuron and Glia Interactions in the Regulation of
Cardiovascular Function by the RAS
In addition to direct effects of ANG II and other RAS
components on neurons, the localization of the RAS elements
to diverse cell types within the CNS brings to light the
possibility that communication between neurons and glia mediates CNS RAS actions. It is a fact that neurons and glial cells
interact with one another on many levels and thereby impact
neurophysiology. Glial cells influence neurotransmitter release
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column of the spinal cord leads to increased sympathetic
outflow to cardiovascular tissues and a rise in blood pressure
(32, 43, 48, 120, 148, 163, 185). Furthermore, the RVLM
contributes to the regulation of barosensitive sympathetic efferents (38), and hyperactivity of RVLM-barosensitive neurons
controlling renal sympathetic nerve activity exerts similar pressor effects. AT1Rs are also localized to the RVLM (2), as well
as other hindbrain cardiovascular control brain nuclei, such as
the NTS (another important integrative site for many homeostatic systems). Activation of AT1R within these hindbrain
regions has been thought to contribute to neurogenic hypertension, via mechanisms that involve abnormalities in the receipt,
processing, or integration of information concerning sympathetic afferents, arterial baroreceptors, chemoreceptors, and
volume receptors (1, 140, 145, 211).
There is evidence that the PRR is localized to neurons and
that its activation influences cardiovascular homeostasis, ultimately contributing to neurogenic hypertension (110, 111,
164). Administration of (pro)renin into the brain of mice
increases blood pressure, an effect that is reversed by the
deletion of the PRR specifically from neurons (111). Further,
neuronal PRR deletion prevents DOCA-salt hypertension in
mice (111). Again, the implication of these previous studies is
that neuronal PRR are critical for the development of hypertension. On the other hand, much like AT1R activation, PRR
can also have diverse effects on blood pressure, depending on
the brain nuclei in which PRR becomes activated. In other
words, PRR stimulation can be pressor or depressor, depending
on the specific population of neuronal PRR that are impacted.
For example, PRR deletion in all neurons and in specific
forebrain nuclei (e.g., supraoptic nucleus) is anti-hypertensive,
suggesting that the PRR within the entire brain and within
these specific areas is pressor (110, 111, 164). On the other
hand, activation of this receptor specifically within the NTS
has also been associated with an antihypertensive response that
is nuclear factor-␬B (NF-␬B)-dependent, but AT1R-independent (215). Additionally, there is also evidence for (pro)renin/
PRR actions within non-neuronal cells of the brain, which will
be discussed in subsequent sections.
It has been suggested that AT1R activation can be opposed
by stimulation of AT2R (20, 82, 177) and by the ACE2-(ANG
1–7)-Mas axis (44, 47, 50, 98, 158). At least under normal,
nonhypertensive conditions, AT2Rs within or adjacent to cardiovascular control nuclei, are exclusively neuronal (42), and
Mas have similarly been localized, in large part to neurons
(60). As would then be expected, these putative cardioprotective limbs of the RAS directly impact the neuronal control of
cardiovascular function. Consistent with this, AT2R activation
via the administration of the selective agonist Compound 21 or
Mas activation via the administration of ANG 1–7 within the
brain reduces blood pressure (20, 22, 64, 69, 208). Conversely,
blockade of either AT2R or Mas specifically in the brain via the
delivery of the AT2R antagonist (PD123,319) or the Mas
antagonist (A-779) elevates blood pressure, as well as sympathetic nerve activity to specific tissues (63, 64, 137). Furthermore, additional studies have extended these findings by determining specific brain nuclei that are involved in the antihypertensive actions of the Mas and AT2R. For example,
overexpression of ACE2, an enzyme required for ANG 1–7
formation, within the NTS (209) or PVN (176) leads to similar
antihypertensive responses. In regard to AT2R, its antihyper-
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ROLE OF CNS RAS, NEURONS, AND GLIA IN CARDIOVASCULAR CONTROL
processes in response to certain threats, thereby, in a sense,
withdrawing their influence. Of particular relevance, this phenotypic shift can be observed within the magnocellular PVN
during hyperosmotic challenges (197). On the other hand, in
response to other threats (e.g., obesity and injury) astrocytes
undergo a phenomenon that is often referred to as astrogliosis,
which is characterized by hyperplasia and hypertrophy of these
cells and can be observed via the upregulation of glial fibrillary
acidic protein (GFAP) and an increased number of GFAPpositive cells within the site of injury (24, 26, 41, 143).
Similarly, the microglial response to injury is characterized by
a phenotypic shift from a “resting state” appearance, in which
they contain long processes that are dynamically surveying the
microenvironment for potential threats, to an “activated state”
in which they respond to a potential threat by transforming into
cells with enlarged cell bodies and ramified processes (102,
130, 167). Upon inury, they also migrate to and infiltrate the
damaged tissue (133, 167, 192). Activated microglial cells then
facilitate neuroprotection by removing debris, clearing dead
cells, and secreting neurotrophic factors. However, chronic
recruitment and activation of microglia can be maladaptive by
contributing to impaired neuronal function or inducing neuronal death, as reviewed by several authors (6, 99, 130, 192). Of
relevance, the “protective” microglia are often designated as
M2 microglia, while the “maladaptive microglia” are often
referred to as M1 microglia. Furthermore, once activated, both
microglia and astrocytes perpetuate a proinflammatory milieu,
and are, thereby, also thought to impact neuronal signaling.
Proinflammatory and immune involvement in communication between neurons and glia. One mechanism by which the
various neuronal and glial cell types of the brain communicate
with one another is via the release and detection of proinflammatory or immune factors (39). Consistent with their roles in
the innate immune system, they express the pattern recognition
Toll-like receptors (TLRs; pattern recognition receptors) that
identify molecules conserved among many pathogens [e.g.,
TLR-4 is well known to recognize lipopolysaccharides (LPS)],
and they are capable of expressing and synthesizing numerous
cytokines and chemokines, as well as their receptors (53, 90).
As a consequence, microglia and astrocytes both sense and
perpetuate a proinflammatory milieu within the CNS, and this
glial-mediated rise in inflammation has a profound impact on
neuronal activity.
Importantly, astrocytes and microglia are both localized to
cardiovascular control centers of the brain, and both lie in close
proximity to preautonomic (39) and to AT1R-containing PVN
neurons. Within these areas, they are capable of sensing and
responding to hypertensive stimuli to impact cardiovascular
function (24, 66, 192). Consequently, it is possible that astrocyte-neuron and/or astrocyte-microglia interactions contribute
to the inflammation within cardiovascular control centers of the
brain that ultimately elevates blood pressure. During experimental hypertension, the PVN, as well as other brain regions
important for regulating sympathetic outflow, such as the NTS,
are infiltrated with additional microglia and astrocytes, the
levels of proinflammatory factors and reactive oxygen species
within these regions rise, and these events have the potential to
influence neuronal activity within these regions (29, 167, 201,
202, 216). This neuroimmune communication between microglia, astrocytes, and neurons has then been suggested to facilitate neurogenic hypertension (30, 39).
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and metabolism, while neurotransmitters and other factors
released by neurons impact the activity of glial cells. Furthermore, since both microglia and astrocytes are considered the
brain’s resident innate immune cells (149), there is potential
for the RAS to initiate inflammatory responses within cardiovascular control centers of the brain via the activation of these
non-neuronal cells, possibly modulating cardiovascular homeostasis.
Cross-talk between neurons, astrocytes, and microglia. Over
recent years, the understanding of brain function has shifted
from a predominant focus on neuron-neuron communication,
to the reinforced appreciation that active cross-talk between the
various cell types within the brain is an imperative component
of signaling within the tissue. There are extensive communications between microglia, astrocytes, and neurons that facilitate the ability of microglia and astrocytes to sense disturbances to the nervous system and to regulate the development,
structure, and function of neural connections (99). The impact
of these glial-neuronal interactions on brain function have been
extensively reviewed elsewhere (4, 179, 191).
Astrocytes have traditionally been considered the support
cells or “glue” of the brain, and this accepted, but passive, role
has often overshadowed the appreciation of their many essential active roles in brain function (153, 203). That being said, it
is currently understood that astrocytes and neurons participate
in a bidirectional communication that is essential for the
coordination of synaptic transmission and the function of
neuronal networks (4). Individual astrocytes contact and oversee hundreds to thousands of dendrites and synapses within
various brain areas and are situated such that they can integrate
a tremendous amount of synaptic activity (28, 74). This positioning allows them to regulate neurotransmitter diffusion into
the extracellular space not only via the formation of a physical
barrier to diffusion, but also via effects on neurotransmitter
uptake (46, 144, 154, 191). For example, they are known to
modulate GABA tone via its removal by the GABA transporter
3 within various neural circuits, including those that regulate
sympathetic outflow and blood pressure (138). It is also established that astrocytes regulate the release of glutamate, ATP,
and other signaling molecules from nerve terminals (139).
Further, astrocytes buffer CNS potassium, remove excess cytotoxic glutamate, and modulate blood flow (8, 71, 149).
Finally, astrocytes impact synaptic activity by themselves releasing “gliotransmitters” (121). Of particular relevance, there
is accumulating evidence for a potential role of astrocyteneuronal interactions in the regulation of cardiovascular function, in particular, and this is discussed in greater depth below.
Microglial cells similarly influence neuronal signaling. They
make contact with synaptic structures and are, thereby, positioned to sense activity within neuronal circuits (200), and gap
junctions between microglia and neurons allow the exchange
of ions and small molecules between these cell types (49, 52).
Further, microglia facilitate synaptogenesis subsequent to brain
injury (13). Additionally, astrocytes and microglia interact with
each other to regulate neuronal function (8, 14, 15, 100, 116).
That is, astrocytes release factors that modulate microglial
activity and vice versa (14, 45, 210).
It is well known that these two glial cell types respond to
severe threats to the internal milieu of the brain, such as injury
subsequent to stroke, by undergoing phenotypic transformations. On one hand, astrocytes are known to retract their
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ROLE OF CNS RAS, NEURONS, AND GLIA IN CARDIOVASCULAR CONTROL
evidence that astrocytes do impact preautonomic neurons
within the PVN in that they regulate the inhibitory GABA tone
onto these neurons, thereby influencing renal sympathetic
nerve activity, an important component of blood pressure
regulation (138).
Another mechanism by which the RAS may impact neuronal-glial interactions is via an escalation of the proinflammatory milieu within cardiovascular control centers (10, 41, 167).
Hypertension produced by chronic infusion of ANG II is
associated with AT1R-mediated increases in microglial activation and cytokine levels in the PVN (167). Furthermore,
accumulating evidence has indicated that the beneficial properties of RAS blockade are attributable, in part, to anti-inflammatory actions (11, 155). That being said, unlike the general
acceptance that ANG II receptors are localized to neurons,
whether or not non-neuronal cells of the brain also express
ANG II receptors under normal conditions in vivo is less clear.
Consequently, whether ANG II impacts astrocytes and microglia directly via receptors expressed on these cell-types or
indirectly via its effects on neuronal receptor activation is a
subject of debate.
In support of direct ANG II actions on non-neuronal cells,
there are studies that have localized AT1R to cultured microglia that were exposed to LPS (127) and to astrocytes both in
culture and in vivo (61, 183, 184). However, as some of these
previous localization studies (61, 183) were conducted using
ANG II receptor antibodies, the presence of the ANG II
receptors on these non-neuronal cell types should be verified
using alternate methodologies (e.g., reporter mice or in situ
hybridization). Further, there is evidence that ANG II can elicit
immune responses via activation of these AT1R (59, 61, 97).
For example, in vitro, ANG II administration impacts cultured
microglia and astrocytes by increasing transforming growth
factor-␤ (TGF-␤) expression, while angiotensin receptor
blockers reduce inflammatory responses to ANG II and other
stimuli (e.g., LPS) (103, 127). Moreover, in vivo, AT1R blockade using candesartan, an angiotensin receptor blocker that
crosses the BBB, leads to reduced inflammatory responses
during immune challenges or hypertensive stimuli within specific brain regions that is often accompanied by decreased
microglial activation (10, 103). However, these in vivo actions
may or may not be due to direct actions on glia.
As discussed in detail above, there are studies that have
determined that ANG II receptors are likely not localized to
glia and are instead exclusively localized to neurons in the
brain (42, 67, 134). Characterization of recently generated
transgenic AT1R and AT2R reporter mice indicate that, under
normotensive in vivo conditions, brain AT1R and AT2R expression is almost solely neuronal (42, 67). Although a lack of
ANG II receptor expression on non-neuronal cells of the brain
may rule out direct effects of ANG II on glial cells, it would
not per se rule out a key role of ANG II in glial cell influence
over cardiovascular homeostasis. It is possible that microglia
(and astrocytes) sense neuronal AT1R stimulation and that this
then triggers their activation [i.e., an indirect mechanism by
which ANG II influences glial cells via secretion of chemotactic factors from neurons (173, 204, 205)]. The prediction is
that this feeds forward to further enhance hypertension, by
promoting the above-described inflammatory response in glia
that then further enhances sympathetic outflow. In this regard,
there is some evidence for such a role for chemotactic proteins
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In regard to cardiovascular function, increases in proinflammatory cytokines within brain nuclei that regulate cardiovascular homeostasis are generally considered to promote sympathetic nervous system activity and increase blood pressure. For
instance, such is the case upon an elevation in proinflammatory
cytokines specifically within the PVN. Blockade of proinflammatory cytokines within the PVN, for example, via the administration of a TNF-␣ receptor antagonist, etanercept, has the
opposite impact on blood pressure (175). Furthermore, elevations in the levels of the anti-inflammatory cytokine, IL-10,
within the PVN similarly reduce blood pressure (167). The
implication is that the proinflammatory actions of ANG II
within the brain may also contribute to the hypertensive actions
of this peptide.
Evidence for astrocyte and microglial involvement in the
neural regulation of cardiovascular function by ANG II and
(pro)renin. Although it is recognized that ANG II can have a
direct impact on neurons to regulate cardiovascular function,
several lines of evidence indicate that the RAS also impacts
cardiovascular function by facilitating the communication between neurons and glia (39). Along these lines, since astrocytes
represent the key cell type within the nervous system that
synthesize angiotensinogen (88, 123, 134, 166, 180), it is
intriguing to hypothesize that astrocyte-generated angiotensinogen itself acts as a signaling moiety to facilitate this
communication. Similarly, as it is evident that astrocytic angiotensinogen is critical for the integrity of the BBB (96), it is
possible that the brain RAS plays a “gatekeeping” role,
whereby it maintains and/or potentiates the access of endocrine
ANG II and other circulating factors to the brain. In this regard,
ANG II derived from astrocytic angiotensinogen has been
found to activate AT1R on endothelial cells to maintain BBB
function (206).
Also of particular relevance, astrocytes and the RAS have
independently been acknowledged to impact the magnocellular
AVP system to influence blood pressure, and it is possible that
an angiotensinergic-neuronal-glial communication impacts
AVP signaling to ultimately regulate cardiovascular function
(34, 46, 115, 191). As discussed above, astrocytes regulate
neuronal function, in part, by influencing neurotransmitter
diffusion into the extracellular space through a variety of
mechanisms involving the formation of a physical barrier to
diffusion and via neurotransmitter uptake (46, 144, 154, 191).
Within the magnocellular region, in particular, astrocytes are
involved in regulating excitatory/inhibitory neurotransmitter
balance through such mechanisms, and the disruption of this
balance is associated with disease conditions that are known to
impact the RAS, such as heart failure (146, 147). For example,
they influence crosstalk between NMDA and GABAA postsynaptic receptors in magnocellular neurons (147). Moreover,
dehydration, which is known to impact the RAS and blood
pressure, is associated with a structural remodeling of the
neuronal-glial interactions within the magnocellular portion of
the PVN, as well as the SON (197), and it is possible that a
modulation of the neuronal-glial interactions within the magnocellular hypothalamus is integral to the RAS regulation of
blood pressure. Furthermore, it is also possible that hypertensive stimuli induce such a remodeling of the astrocyte-neuron
interactions within the preautonomic portion of the PVN and,
thereby, also allows for altered angiotensinergic-neuronal-glial
interactions [e.g., obesity (41)]. Along these lines, there is
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ROLE OF CNS RAS, NEURONS, AND GLIA IN CARDIOVASCULAR CONTROL
tured astrocytes of rats, an effect that is potentiated in astrocyte
cultures generated from hypertensive rats (152).
On the other hand, there are several lines of evidence that
have linked the neuroprotective effects of AT2R activation and
of the ACE2-(ANG 1–7)-Mas axis to their ability to alter the
interactions between neurons and non-neuronal cells in the
brain (12, 198). For example, AT2R activation using the
selective AT2R agonist Compound 21 attenuates microglial
responses during autoimmune encephalomyelitis (81), and
there is some evidence that astrocytic AT2R correlates with
BBB breakdown during CNS inflammation (181), implying
that AT2R may also play a role in the access of the peripheral
RAS to the CNS. In regard to the ACE2-(ANG 1–7)-Mas axis,
in addition to Mas’s documented expression in neurons, there
is also evidence that this receptor is localized to microglia
(150) and that its activation impacts microglial responses to
stroke, implying that activation of this protective RAS either
directly or indirectly influences these non-neuronal cells. It is
possible that the putative protective effects of these systems in
the CNS control of cardiovascular function similarly involve
astrocytes and microglia (70).
Conclusions and Hypothesis
Although it has been suggested that ANG II receptors
located on glial cells mediate certain cardiovascular actions of
ANG II, we propose rather that cooperation between neurons
and glia is integral to the RAS influence over the brain control
of cardiovascular function under normal and hypertensive
conditions. As discussed throughout this review, this premise
stems, in part, from the realization that the components required for ANG II synthesis and action are not confined to a
single cellular compartment within the CNS and are instead
localized to diverse cell types throughout the tissue. Further,
despite numerous research efforts to localize ANG II receptors
to non-neuronal cells in the brain, their presence on cells other
than neurons of the CNS in vivo is not definitively supported
by the literature, particularly under normotensive conditions. In
spite of this, there are numerous lines of evidence indicating
that AT1R activation does, indeed, impact microglial activation
and astrogliosis and that this is associated with cardiovascular
dysfunction.
This profound impact of the ANG II on microglia and
astrocytes coupled with the apparent lack of AT1R expression
within these cell types under normal baseline conditions, further reinforces the appreciation of a probable intricate relationship between microglia, astrocytes, and ANG II receptorcontaining neurons. Along these lines, we have previously
determined, that both astrocytes and microglia lie in close
proximity to preautonomic PVN neurons (39) and are, therefore, positioned to regulate sympathetic outflow. Here, we
further determined that in normotensive Sprague-Dawley rats,
microglia and astrocytes, although they themselves lack AT1aR
mRNA under normotensive conditions, are localized in close
proximity to AT1aR-containing neurons within the PVN. Consequently, these AT1aR-containing neurons within the PVN are
similarly positioned to interact closely with glial cells and
perhaps respond to glial cell-generated or circulating RAS
peptides, and it is possible that similar interactions are present
in other cardiovascular control nuclei, as well.
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such as CC-chemokine ligand-2 (CCL2), as well as stromal
cell-derived factor 1 and high-mobility group box 1 in these
processes (168, 173, 204, 205).
There are several studies that would be congruent with either
a direct or indirect influence of AT1R activation on microglia
or astrocytes (40 – 42, 167, 192). For example, a study conducted by our research group revealed that the central administration of minocycline, an anti-inflammatory antibiotic that
reduces microglial activation also decreases ANG II-induced
hypertension (167). Furthermore, deletion of AT1R from neurons within the PVN of mice, leads to reduced microglial and
inflammatory responses that occur subsequent to long-term
high-fat diet consumption (40, 41, 192).
It is also possible that during hypertension, the expression
pattern of AT1R changes and that microglia and/or astrocytes
begin to express the receptor when challenged. Although, as
described above, ANG II receptors are not detected in microglia or astrocytes of normotensive rodents under baseline
conditions in situ (42, 67), some immunohistochemical studies
have revealed localization of AT1R, AT2R, and ANG II labeling in microglia or astrocytes of the ischemic brain or in brains
collected from rodents during other pathological conditions
(89, 207). As mentioned throughout this review, however, the
unreliability of many ANG II receptor antibodies (9, 79) has
led to a hesitance to rely solely on immunohistochemical data
to conclude that ANG II receptors are localized to nonneuronal cells of the brain. Therefore, it will be necessary to
verify these results using alternative localization techniques. In
this regard, using another approach to determine the role of a
potential glial AT1R receptor population in cardiovascular
function, Isegawa et al. (89) recently determined that mice that
have undergone Cre/Lox-mediated deletion of AT1R from
GFAP-containing cells have an improved prognosis when
subjected to myocardial infarction-induced heart failure. In
particular, they found that this “knockout” mouse did not
exhibit the increase in AT1aR mRNA or protein (IHC and
Western blot analysis) within the brain stem that wild-type
mice exhibit in response to MI-induced heart failure. Importantly, under baseline, non-MI-induced heart failure, conditions, there was no difference in AT1aR. The implication is that
astrocytic AT1aR is increased in response to heart failure and
that this increase contributes to heart failure-induced mortality.
Future studies need to be conducted to definitively determine
the localization of ANG II receptors during such pathological
conditions. Nonetheless, the plasticity of ANG II receptor
expression in non-neuronal cell-types of the brain during disease states is an interesting potential mechanism by which
ANG II/glial interactions may impact cardiovascular function.
Such plasticity of ANG II receptor expression in non-neuronal
cells may also be induced during the production of cell cultures, potentially explaining the observations that have demonstrated the presence of AT1R on microglia and astrocytes
within in vitro models (127, 189).
As with ANG II, there is also evidence suggesting that
(pro)renin impacts the non-neuronal cells in the brain, either
directly or indirectly, to ultimately influence neuronal function.
In this regard, (pro)renin elicits a direct proinflammatory action
on microglial cells, mediated through NF-␬B and potentiated
by pretreatment with ANG II (169). Furthermore, we have
found that (pro)renin exerts proinflammatory actions in cul-
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II-dependent and -independent effects and ultimately increase
sympathetic nerve activity and blood pressure (Fig. 2A). This
action of (pro)renin may involve glial effects on RAS components to assist in the generation of ANG II. During hypertension (Fig. 2B), we expect that the elevation in the CNS ANG
II leads to increased activation of neuronal AT1R in BBBprotected brain nuclei, with subsequent activation of preautonomic neurons to augment sympathetic outflow and blood
pressure. Furthermore, we postulate that during hypertension,
activation of neuronal AT1R leads to the secretion of certain
factors (e.g., the chemotactic protein CCL2), which then bind
to their receptors (e.g., CCR2) on microglia and stimulate their
migration toward these neurons. This hypothesis has been
described in detail in a previous review (39). Our model also
incorporates the possibility that a certain plasticity exists in
regard to the cellular localization of the AT1R in the brain,
whereby under cardiovascular pathologies, AT1Rs come to be
expressed on astrocytes and microglia (Fig. 2B). The hypothesis is then that activation of these non-neuronal AT1R directly
facilitates astrogliosis and microglial activation, leading eventually to a perpetuation of neurally mediated cardiovascular
dysfunction. Finally, we predict that in addition to enhanced
neuronal effects during hypertension, (pro)renin acts via PRR
on astrocytes and microglia to elicit astrogliosis and microglial
activation, and subsequent neuronal activation via paracrine
interactions.
Perspectives and Significance
Collectively, we believe that these RAS-mediated increases
in neuronal, microglial, and astrocyte activity contribute to the
perpetuation of neurogenic hypertension. Despite tremendous
research efforts, hypertension and the often consequential morbidity or mortality associated with cardiovascular pathologies
remain an immense problem for our society. Taken together,
the reviewed studies highlight a promising avenue for the
development of antihypertensive therapeutics. These studies
suggest that one potential contributing mechanism to these
pathologies is the RAS-mediated interactions between neurons
and glia within cardiovascular control centers of the brain.
These interactions are now an area of active research that may
lead to new and innovative ways to combat treatment-resistant
hypertension.
GRANTS
This work was supported by National Institutes of Health Grants HL033610 (to C. Sumners), HL-076803 (to C. Sumners), HL-093186 (to C.
Sumners), HL-096830 (to E. G. Krause), F32-HL-116074 (to A. D. de Kloet),
and K99-HL-125805 (to A. D. de Kloet).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
Fig. 2. Hypothetical model for the roles of neurons and glia in the central
nervous system’s actions of the renin-angiotensin system in normotensive (A)
and hypertensive (B) conditions.
Author contributions: A.D.d.K. and C.S. conception and design of research;
A.D.d.K. and M.L. performed experiments; A.D.d.K. analyzed data; A.D.d.K.
interpreted results of experiments; A.D.d.K. prepared figures; A.D.d.K. drafted
manuscript; A.D.d.K., M.L., V.R., E.G.K., and C.S. edited and revised manuscript; A.D.d.K., M.L., V.R., E.G.K., and C.S. approved final version of
manuscript.
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Another important component of the RAS-neuron-glia interactions in cardiovascular control is that during hypertension,
the activity of the RAS actions within the CNS rises. This
elevation in central RAS actions is due to an increase in ANG
II synthesis within the CNS and/or an increase in peripheral
RAS access to the CNS. In regard to the CNS synthesis of
ANG II, the PRR plays a key role in this and then in the
subsequent activation of CNS AT1R. That being said, PRR’s
influence over the neural control of blood pressure extends
beyond its ability to increase ANG II levels locally, within
cardiovascular control nuclei. That is, PRR activation is also
linked to independent intracellular signaling cascades that
facilitate neurogenic hypertension. Furthermore, PRR is likely
expressed on neurons, microglia, and astrocytes during both
normotensive and hypertensive conditions and, therefore, also
has the potential to both directly and indirectly influence the
neuronal-glial influence over cardiovascular function.
Regardless of the source of the ANG II within the brain, we
propose the following model to help explain the respective
roles of neurons and glia in the cardiovascular actions of RAS
components under normal and hypertensive conditions. First,
under normotensive conditions ANG II activates neuronal
AT1R to increase sympathetic nerve activity and blood pressure (Fig. 2A). We further propose that during the normotensive state, (pro)renin can influence neuronal PRR to exert ANG
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ROLE OF CNS RAS, NEURONS, AND GLIA IN CARDIOVASCULAR CONTROL
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