Cardiovascular Neuroendocrinology: Emerging Role for Neurohypophyseal Hormones in Pathophysiology

Abstract

Arginine vasopressin (AVP) and oxytocin (OXY) are released by magnocellular neurosecretory cells that project to the posterior pituitary. While AVP and OXY currently receive more attention for their contributions to affiliative behavior, this mini-review discusses their roles in cardiovascular function broadly defined to include indirect effects that influence cardiovascular function. The traditional view is that neither AVP nor OXY contributes to basal cardiovascular function, although some recent studies suggest that this position might be re-evaluated. More evidence indicates that adaptations and neuroplasticity of AVP and OXY neurons contribute to cardiovascular pathophysiology.

The hypothalamo-neurohypophyseal system (HNS) consists of magnocellular neurosecretory cells (MNCs) located in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus (1). These neurons, along with accessory neurosecretory cells in the lateral hypothalamus, project to the posterior pituitary. From the posterior pituitary, the axon terminals of these neurons release the peptide hormones into the peripheral circulation (Fig. 1). Early studies of pituitary extracts demonstrated that they affected blood pressure (2, 3), urine excretion (4), parturition (5), and lactation (6). These classical endocrine effects were the focus of how the 2 hormones, arginine vasopressin (AVP) and oxytocin (OXY), were studied until much of the field shifted toward their behavior-associated actions as neuromodulators (7–9).

Figure 1.

Magnocellular neurosecretory cells located in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus project to the posterior pituitary where arginine vasopressin (AVP) and oxytocin (OXY) are released into the peripheral circulation. AVP acts on the kidneys to produce antidiuresis and on blood vessels to increase blood pressure. OXY produces uterine contractions that facilitate parturition and stimulates the milk ejection reflex. (Created with BioRender.com).

Among these classical functions, the cardiovascular effects of AVP and OXY have not been as widely investigated as their other actions. Share (3) suggested that there were several reasons why this is true for AVP. One of the foremost reasons is that hypothalamic diabetes insipidus is not normally associated with hypotension. Similarly, patients with the syndrome of inappropriate antidiuretic hormone secretion do not typically present with hypertension. Therefore, the physiological relevance of the pressor effects of vasopressin has been questioned (10, 11). Similarly, OXY appears to influence cardiovascular function more as a neurotransmitter in the central nervous system than as a hormone (12, 13). Recent studies suggest that, instead of normal physiology, AVP and OXY could be more involved in homeostasis and pathophysiology of the cardiovascular system.

AVP and Blood Pressure Regulation/Cardiovascular Function

AVP contributes to blood pressure homeostasis, and its release is stimulated by increased blood osmolality and decreased blood volume that occurs as a result of dehydration, hemorrhage, vasodilatory shock, and other physiological challenges (14–17). Changes in plasma osmolality and/or sodium are detected by osmoreceptors located in the circumventricular organs which activate MNCs located in the PVN and SON and by the MNCs themselves which are intrinsically osmosensitive (16). The effects of AVP are mediated by G protein–coupled receptors, with there being 2 major subtypes of AVP receptors: (1) V1 receptors, further subdivided into V1a and V1b, mediating vasoconstriction and corticotrophin secretion, respectively, and (2) V2 receptors, involved in fluid reabsorption by the collecting duct of the kidneys (18–21). V1a receptor–deficient (V1aR–/–) rats are hypotensive, have impaired arterial baroreceptor reflex activity, decreased blood volume, and decreased sympathetic nerve activity (22), and AVP-deficient rats have blunted blood pressure recovery following hemorrhage (23). Terlipressin (analog of AVP) and Selepressin (V1a receptor agonist) are being studied for their use in treating vasodilatory shock as AVP has become an important therapeutic target for this disorder (15, 24, 25).

Baroreceptors are primary sensory neurons that innervate the carotid sinus and the aortic arch and are activated by increases in blood pressure (26). Baroreflex stimulation of the vagus (X) and glossopharyngeal (IX) nerves activates the nucleus of the solitary tract (NTS), which distributes this information to the caudal ventrolateral medulla, nucleus ambiguus, and the hypothalamus (26, 27). In addition to autonomic regulation, early studies indicated baroreceptors regulate AVP release since baroreceptors denervation produced an acute elevation in circulating levels of AVP (28, 29). Furthermore, vagotomy, removal of aortic and cardiopulmonary baroreceptors, and carotid occlusion also increase circulating levels of AVP (3, 30, 31). Acute activation of baroreceptors inhibits the activity of putative AVP neurons, and these inhibitory effects are mediated by the diagonal band of Broca (DBB) (32–34) and the perinuclear zone (PNZ) (35, 36). Therefore, the stimulation of peripheral baroreceptors activates the DBB that projects to PNZ, a region adjacent to the SON, inhibiting the activity of AVP neurons. The inhibitory effects of baroreceptors on SON neurons seem to be mediated by the neurotransmitter gamma aminobutyric acid (GABA) (32). The blockade of GABA receptors at the SON or PVN prevents the inhibition of AVP neurons when the baroreceptors are stimulated (32, 37, 38). Furthermore, noradrenergic neurons in the locus coeruleus may also be involved in the baroreflex activation of the DBB (39). The A1 region of the ventrolateral medulla contributes to AVP release stimulated by baroreceptor unloading or the activation of low volume receptors (17).

Humoral signals can also stimulate AVP release, resulting in acute or chronic changes in blood pressure. Chronic osmotic stimulation associated with either deoxycorticosterone acetate (DOCA) salt hypertension or salt loading activates AVP neurons leading to increased blood pressure in male rats (40, 41). Increased activation of AVP neurons also contributes to hypertension in rats given angiotensin II (Ang II) and salt loading (42). Circulating Ang II acts at circumventricular organs (eg, the subfornical organ) and regulates blood pressure by multiple mechanisms, including AVP release (43). Recent studies using sophisticated genetic approaches have demonstrated that a brain angiotensin system may also contribute to AVP release and blood pressure regulation (44, 45). Together these studies demonstrate that neural and humoral signals related to cardiovascular function can alter AVP release in physiological and extraphysiological contexts.

In the central nervous system, AVP neurons from parvocellular PVN project to sympathetic premotor neurons in the rostral ventrolateral medulla and sympathetic preganglionic neurons in the spinal cord (26). Intrathecal injections of AVP increase blood pressure and sympathetic nerve activity (46–48). Studies using vasopressin-deficient Brattleboro rats indicate that, although AVP can contribute to sympathetic regulation, its absence can be compensated for by glutamate, and AVP may contribute to long-term regulation of blood pressure as a neurotransmitter (48). More recently, the dendritic release of AVP in the PVN has been shown to influence sympathetic nerve activity and blood pressure (49). In male rats, V1 receptors in the PVN contribute to hypertension associated with chronic stress (50). These observations are consistent with AVP contributing to long-term cardiovascular control and pathophysiology.

OXY and Blood Pressure Regulation/Cardiovascular Function

In addition to the brain, OXY is synthesized by the heart and large vessels such as the aorta and vena cava and mediates chronotropic effects on the heart and influences vascular tone (51). There is only 1 OXY receptor, which is coupled to Gq/11 protein and can be found in mammary and uterine smooth muscle, heart, kidney, brain, and vasculature (18–21). Despite that, OXY can also bind to AVP V1a receptors, causing vasoconstriction (52). Like AVP, OXY may not directly contribute to maintaining blood pressure in normal conditions. Some of the cardiovascular effects of OXY are indirect, mediated by its effects on atrial natriuretic peptide (ANP) release and nitric oxide (53, 54). ANP is a potent diuretic and natriuretic hormone isolated from the heart that affects blood pressure and electrolyte homeostasis (55). OXY increases plasma ANP and sodium excretion in rats (56, 57). Genetically modified animals that have increased plasma ANP are hypotensive, while ANP or OXY knockout mice have increased blood pressure (58–60). In rats, hypophysectomy completely inhibits ANP responses to blood volume expansion, indicating a link between HNS and ANP release (61). In the brain, OXY can act at the locus coeruleus, NTS, and dorsal motor nucleus of the vagal nerve, decreasing blood pressure and heart rate, possibly via α2-adrenoreceptors (12, 62, 63).

AVP and OXY in Control of the Blood Volume and Natriuresis

AVP and OXY are central to the regulation of blood volume and electrolyte homeostasis. A decrease in blood volume is a major stimulus for AVP release, and it is mediated via baroreceptor and volume receptor pathways (64–66). In the rat, OXY increases urinary sodium excretion at physiological concentrations (67). However, this effect is species specific (68). Plasma volume expansion stimulates the release of OXY, while AVP secretion is inhibited to allow restoration of plasma volume to homeostatic levels. Circulating OXY has a secondary effect on natriuresis by stimulating the release of ANP from the atrium, which also increases renal sodium excretion (69, 70). Increased secretion of AVP in some pathophysiological states can lead to an increase in water retention resulting in dilutional hyponatremia (71, 72), affecting cellular functions and the maintenance of homeostasis (73). Studies have shown that in salt-loaded rats there is a failure of the inhibitory mechanism for AVP secretion (74). This has been linked to an increased expression of brain-derived neurotrophic factor (BDNF) in the SON MNCs, leading to the reversal of the chloride gradient (74, 75). It is possible that a similar mechanism is at play in other states of increased AVP release, such as liver disease, heart failure, and even pregnancy.

Sex Differences in AVP and OXY and Cardiovascular Function

While the general biology of AVP and OXY as hormones is well understood, little is known about the existence or implications of any potential sex differences with respect to their biology. Sex differences in AVP and OXY synthesis and projections in the brain were reviewed in detail by Dumais and Veenema (76). They noted that while AVP synthesis is often sexually dimorphic, the functional significance of such dimorphism is unclear. They also noted that while sex differences in OXY immunoreactivity and mRNA expression have been reported in rodent hypothalamic nuclei with females showing higher levels than males, it remains unknown whether these differences translate into differences in OXY release (76). In most species, there are no sex differences reported for AVP or OXY expression in the PVN or SON, regions important in HNS communication with the cardiovascular system. Additionally, where sex differences exist, they appear to be species specific (76–78). Overall, limited sex difference research exists for both AVP and OXY release.

With expanding research suggesting AVP and OXY having a more substantial influence on pathophysiology, it is beneficial to consider the influence of sex in disease models. A few groups have reported sex differences in the regulation of AVP and OXY release that were either not mentioned in or published after Dumais and Veenema (76) which addressed this point. Results from early studies by Stone et al. suggested the influence of gonadal steroid hormones in adrenoreceptor-mediated control of AVP release where plasma AVP levels rose 4 times higher in the high estradiol phase (proestrus) of the estrous cycle when than low estradiol phases and males in response to intracerebroventricular (ICV) injection of norepinephrine (79). The same group later reported sex differences in central cholinergic and angiotensinergic mechanisms in the regulation of AVP release after finding plasma AVP concentration of male rats increased twice as much as female rats after ICV injection of the cholinergic agonist, carbachol; however, the increase in plasma AVP concentration of males was only half that of females after ICV injection of Ang II (80). OXY release has also been shown to be affected by gonadal steroid hormones. Scott et al. (81) revealed a tyrosine hydroxylase–expressing neuronal cluster in mice having monosynaptic inputs to OXY neurons in the PVN, which promoted OXY release in females but not in males. Other groups found sex differences in stress-induced OXY release in which short-term immobilization was used as a stressor resulting in increased plasma OXY levels in males, which was exacerbated after orchidectomy. Stress-induced increases in plasma OXY were also observed in females. However, that increase was unchanged when induced following gonadectomy in contrast to what was observed in the males (82–84). The acute immobilization used in these studies correlates to the human feelings of helplessness and is often used to model post-traumatic stress disorder (85). These studies could provide some insight into cardiovascular effects since sex differences in hypothalamic–pituitary–adrenal (HPA) axis response to stress have been linked to cardiovascular disease (86–88). Consistent with this theory, Dempster et al. report that children who experience adverse childhood experiences such as maltreatment and severe household dysfunction demonstrate altered HPA axis activity, which is associated with chronic changes in AVP and increased risk of chronic illness including cardiovascular disease (89). In regards to homeostatic stresses, a recent study from our group reported sex differences in the regulation of both AVP and OXY release in bile duct–ligated rats, a rodent model of hyponatremia associated with cirrhosis (90). Despite these reported findings, much remains to be uncovered regarding sex differences in the regulation of AVP and OXY release, particularly in the context of cardiovascular function.

AVP and OXY Receptors

To better understand the implications of changes to AVP and OXY regulation in cardiovascular function and disease, it is important to consider the expression of and main effects mediated by their receptors, which will be reviewed in the following sections based on location.

Cardiovascular System

In the heart, the V1a receptor is predominantly expressed. Located on the cardiac myocytes, V1a receptors contribute to the maintenance of physiological blood pressure by maintaining circulating blood volume and baroreflex sensitivity (91). While V1a receptors located in the heart play only a moderate role in the homeostatic maintenance of blood pressure, multiple animal models support the idea that cardiac V1a receptors play a significant role in the development and advancement of chronic heart failure (92, 93). In fact, cardiac V1a receptor expression more than doubles in patients with end-stage heart failure, making it a strong target candidate for the treatment of heart failure (94, 95).

V1a receptors are also expressed in vascular smooth muscle and blood vessels, affording them a significant role in regulating blood pressure (96). Here, the receptors mediate a vascular contractile effect in response to AVP (91). The contractile effect occurs via the phosphatidylinositol–bisphosphonate pathway, which leads to increases in intracellular calcium. Seemingly contradictory, both AVP and OXY can induce a vasodilatory effect in vascular endothelial cells through nitric oxide release (74), a result of OXY receptor activation (97, 98). OXY receptors have been identified in endothelial cells and are shown to have an equal affinity for both AVP and OXY.

Brain

The OXY receptor, a G_q-coupled receptor, has been identified in many different brain regions, including olfactory bulbs, anterior olfactory nucleus (AON), olfactory tubercle, nucleus accumbens, prelimbic cortex, ventral subiculum, central nucleus of the amygdala, ventromedial nucleus of the hypothalamus, cingulate cortex, dorsal motor nucleus of the vagus, nucleus tractus solitaries, among other areas. In the brain, OXY and V1 receptors (both V1a and V1b) are largely known to modulate social behaviors as opposed to normal cardiovascular function (76, 99–101). It is noteworthy though that brain V1 and OXY receptors have been implicated in various aspects of cardiovascular dysfunction or pathophysiology (eg, hypertension (102, 103), myocardial infarction (104, 105), cardiovascular response to stress (106, 107), and body fluid homeostasis (108)). Sex differences have been reported in OXY receptor and V1a receptor binding density with V1a receptors consistently higher in male rats than female rats and OXY receptor differences being region specific; however, the sex differences were less prominent than age differences (101). The OXY receptor gene contains a palindromic estrogen response element, allowing expression to be regulated by estrogens. Specifically, estrogen has been shown to increase OXY receptor expression in the male and female rat brains. According to that same study, AVP receptors in the brain are unaffected by gonadal steroid hormones (109).

Kidney

OXY receptors are present in the kidney, where they have been shown in rats to have a natriuretic response caused mainly by decreasing sodium reabsorption (67). Renal OXY receptor expression is thought to be, at least in part, influenced by estradiol and estrogen-induced water and solute reabsorption is mediated by renal OXY receptors (110, 111). The primary AVP receptor located in the kidney is the V2 receptor, and its mRNA expression has been shown to be significantly higher in female rats than in males (112). Consequently, female rats have potentially greater sensitivity for AVP-induced antidiuresis and susceptibility to blood volume disorders that can lead to other cardiovascular complications (112). A possible reason for the observed sex difference in V2 receptors is that the avpr2 gene is located in a region with a high chance of escaping inactivation on the X chromosome, which may lead to higher expression in females than males (113). The V2 receptor is important in maintaining normal fluid balance, and thus antagonistic drugs such as tolvaptan are the focus of treating hyponatremia associated with heart failure (114).

Plasticity

The activity of MNCs in the SON and PVN has been widely studied (115) and is influenced by both intrinsic and extrinsic mechanisms. Activation of these mechanisms can induce structural changes, not only in MNCs but in astrocyte morphology as well. Furthermore, synaptic inputs can induce synaptic plasticity and influence gene expression. Ultimately, these stimuli-induced changes in structure, synaptic plasticity, and gene expression in the MNCs regulate the release of AVP and OXY into the systemic circulation.

Structural Plasticity

The MNCs in the SON and PVN exhibit an intrinsic sensitivity to osmolality (116, 117). The osmosensitivity of the MNCs involves the activity of the mechanosensitive cation channel transient receptor potential vanilloid type 1 (TRPV1) (118, 119). In addition, MNCs express TRPV2 in the SON and PVN (120) and TRPV4 in the SON (120, 121), contributing to the inappropriate AVP release in a bile duct ligation model of hyponatremia. Furthermore, the expression of TRPV4 has been shown to be sensitive to ANG II (122). TRPV1 channels interact with structural proteins in the cells as part of their role in osmosensation. The osmosensitivity of MNCs involves the function of actin (123, 124) and microtubules (125). ANG II has been shown to influence actin density and enhance the response to osmotic challenges (126). Meanwhile, microtubules have been shown to interact with TRPV1 channels via β-tubulin (127, 128). Furthermore, the density of microtubules in the AVP cells is increased following salt loading (129).

Morphological plasticity influencing the function of the HNS is not limited to the MNCs and has also been studied in glial cells (130, 131). Retraction of astrocytic coverage observed in the SON and PVN during parturition, lactation, and dehydration can impact the synaptic function of MNCs in several ways (132, 133). This retraction can influence the clearance and diffusion of neurotransmitters as well as increase the availability of both glutamatergic and GABAergic synapses.

Synaptic Plasticity

Glutamatergic synapses in the SON are structurally changed following chronic salt loading (134, 135). Salt loading is associated with a decrease in NMDA receptor subunit expression (136) and altered Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid (AMPA) subunit expression (137) that favors GluA1 and thus an increased calcium permeability. While this increased AMPA receptor–mediated calcium entry may induce excitotoxicity in other cell types, MNCs have been shown to have an increased resistance to neurotoxicity (138). Water deprivation is also associated with increases in phosphorylation of N-Methyl-D-Aspartic Acid (NMDA) receptor subunits (139).

Salt loading has been shown to alter GABA-mediated inhibition in the SON. Osmotic stress can change the structure of the GABA synapse (134, 140). Osmotic stress can alter chloride homeostasis, rendering GABA excitatory (40, 74, 141, 142). Increases in AVP release during salt loading are associated with an increase in BDNF in the SON (75), and BDNF appears to contribute to the changes in the valence of the GABA response (40, 74). Inappropriate AVP release associated with liver cirrhosis is also due in part to an upregulation of BDNF in male rats (143), while its effect on chloride transport remains to be determined. This effect of salt loading on AVP release contributes to a chronic increase in blood pressure (40). Similar changes in the function of AVP neurons have been reported in other models of hypertension, such as DOCA salt (41, 141), chronic ANG II (144), and Cyp1a1-Ren2 transgenic rats (145). The shift of GABA inhibition to excitation blunts the normal baroreceptor inhibition of AVP MNCs (145). Similar changes in GABA function have also been observed in presympathetic PVN neurons (146). The relevance of these mechanisms to human essential hypertension or heart disease has not been directly tested.

The epithelial sodium channel (ENaC) has been shown to regulate blood pressure through the reabsorption of Na⁺ at the distal portion of the nephron of the kidney (147). ENaCs have also been located in the AVP cells of the SON and PVN (148) and may play a role in salt-sensitive hypertension. ENaC in AVP neurons seems to contribute to a Na⁺ leak current at resting membrane potentials (149) but does not seem to influence the burst firing patterns characteristic of AVP cells (150). Interestingly, while high salt intake reduced the expression of ENaC in the kidney, high salt increases the expression of ENaC in the SON (150).

Repeated ICV injections of AVP produce sensitization of both its cardiovascular and behavioral effects (151, 152). Stress paradigms that cause central AVP release have also been shown to produce behavioral sensitization and cross-sensitization with corticotropin-releasing hormone (153). While this sensitization may not represent synaptic plasticity in a traditional sense, it is due to increased V1 receptor transduction (154). AVP and OXY were among the first peptides shown to be released from dendrites (155–157). Dendric release of AVP could sensitize V1 receptors in the SON and PVN, leading to potentiated cardiovascular responses.

Changes in Gene Expression

Using RNA sequencing methods, novel genes have been identified in the SON and PVN that are differentially regulated in response to sodium depletion (158), dehydration (159), and salt loading (159). This approach has identified a number of novel genes in the SON and PVN that are potentially related to body fluid homeostasis, such as creb3l1, a cAMP response element protein that has been shown to regulate avp transcription (160, 161).

A different approach has been used for another transcription factor that likely influences the function of MNCs. In the SON and PVN, 48 hours of water deprivation increased c-Fos and FosB expression. This increase could be reversed following 2 hours of rehydration (162, 163). Water deprivation has also been shown to increase the expression of a member of the AP-1 family of transcription factors, JunD, in the SON, with most of the JunD colocalizing with AVP neurons (164). Furthermore, c-Fos and FosB have been shown to be upregulated in the SON and PVN in response to volume expansion (165). ΔFosB was also increased in AVP and OXY cells in the SON following bile duct ligation, and blockade of the ΔFosB increase (using ΔJunD) attenuated the dilutional hyponatremia (166). The increased ΔFosB seen following bile duct ligation is not dependent on circulating ANG II acting at the subfornical organ (167). The genes regulated by ΔFosB have not yet been determined.

Both AVP and its receptors are regulated by epigenetic mechanisms. For example, increased methylation of CpG (cytosine-phosphate-guanine) sites is a common inhibitory epigenetic mechanism. DNA demethylation and de novo methylation of CpG residues in the proximal avp promoter occurs following dehydration but not salt loading in rat SON (168). Early-life stress in mice leads to epigenetic hypomethylation of a key regulatory region of the avp gene in the PVN. This modulation results in a persistent upregulation of avp expression in the PVN parvocellular division leading to a sustained hyperactivity of the HPA axis (169). Hypermethylation in the proximal promoter of the V1a receptor and protein kinase C isoform β (PKCβ) genes of the umbilical vein and placental vessels deactivates their transcription and ultimately leads to the attenuation of vasoconstriction responses to AVP in pre-eclamptic pregnancy (170, 171). This suggests that the epigenetic mechanisms that influence the expression of AVP and its receptors are determined by the physiological challenge applied to the system as well as the age of the organism.

Changes in Excitability

In animal models of heart failure and hypertension, increased activity of the MNCs that might be contributing to elevated circulating AVP has been demonstrated. In MNCs of rats with heart failure, the increased activity might be explained by reduced expression of the small conductance Ca²⁺-activated K⁺ (SK) channel and blunted coupling between SK channel and NMDAR (172, 173). The magnitude of medium spike after-hyperpolarization, a determinant of repetitive firing properties in AVP and OXY MNCs, depends on this SK channel. This channel is functionally coupled to NMDAR to form a negative feedback loop to NMDAR membrane depolarization.

In rats with renovascular hypertension, the activity of the MNCs is increased due to greater endogenous glutamate tone, which activates extrasynaptic NMDA receptors and tonically inhibits A-type K⁺ current (I_A). (174). In the same model, NMDA receptor–mediated calcium signaling is also altered spatiotemporally to be more prolonged and larger than normal as the ER Ca²⁺ uptake mechanism is blunted, therefore contributing to the increased firing rate of MNCs (175). The activity of AVP and OXY MNCs can also be stimulated by prorenin through its prorenin receptor, an effect that also involves inhibition of A-type K⁺ current (I_A) (176, 177). This prorenin effect will, in turn, elevate the circulating level of AVP in the DOCA salt hypertension model (178).

Summary

The participation of AVP and OXY in normal cardiovascular function remains controversial. This could be a function of the redundant mechanisms that regulate blood pressure. What is clearer is that activity-dependent changes in the function of AVP MNCs can negatively influence cardiovascular function and body fluid balance. Stress-induced plasticity has been demonstrated to facilitate adaptation in the HPA axis (179) and sensitize blood pressure regulatory systems (180, 181). Activity-dependent changes in cell morphology, synaptic strength, and gene expression in the SON and PVN come together to alter the excitability and firing patterns of AVP and OXY neurons to ultimately change the release of these neuropeptides into the systemic circulation to affect the peripheral cardiovascular function or the local parenchyma changing autonomic function (49). Changes in gene expression and possibly epigenetic mechanisms may further influence the excitatory/inhibitory balance of the MNCs or alter their responses to subsequent challenges. While this plasticity may normally function to help maintain homeostasis, it may contribute to cardiovascular disease (Fig. 2). The outcome of these processes may ultimately be determined by the sex of the individual. For example, AVP has been identified as contributing to the pathogenesis of pre-eclampsia (182) which is characterized by hypertension in late pregnancy.

Figure 2.

Homeostatic challenges activate central pathways that induce plasticity in the MNCs of the SON and PVN. This plasticity influences the release of AVP and OXY both centrally and into systemic circulation and contributes to cardiovascular regulation. SON, supraoptic nucleus; mPVN, paraventricular nucleus magnocellular division; pPVN, paraventricular nucleus parvocellular division. The sex of the individual would influence each of these processes. (Created with BioRender.com).

Blocking AVP receptors improves fluid balance in patients with either liver disease or congestive heart failure (183–186), but these effects have not always translated into better clinical outcomes (184). As indicated above, the dendritic release of peptides from MNCs influences the activity of autonomic networks and possibly other neuroendocrine systems (49, 187). This suggests that plasticity in MNCs influences other physiological endpoints that impact cardiovascular function. In male rats, V1 receptors in the PVN contribute to hypertension associated with chronic mild stress paradigm (50). Activation of the V1 receptors associated with mild chronic stress in this paradigm could be due to dendritic release of AVP, and intermittent activation of these receptors could cause sensitization of the cardiovascular and endocrine responses that ultimately lead to hypertension. It is known that female rats tend to have greater neuroendocrine responses to acute stress than male rats, but sex differences in chronic stress are not as well characterized (88). Improving clinical outcomes might require a better understanding of how homeostatic mechanisms are converted into pathophysiology by neuroplasticity and how these processes are determined by the sex of the organism in addition to targeting receptors that regulate end-organ function.

Glossary

Abbreviations

AON

anterior olfactory nucleus

AVP

arginine vasopressin

BDNF

brain-derived neurotrophic factor

DBB

diagonal band of Broca

ENaC

epithelial sodium channel

HNS

hypothalamo-neurohypophyseal system

HPA

hypothalamic–pituitary–adrenal

ICV

intracerebroventricular

MNC

magnocellular neurosecretory cell

OXY

oxytocin

PNZ

perinuclear zone

PVN

paraventricular nucleus

SON

supraoptic nucleus

Additional Information

Disclosures : The authors have nothing to disclose.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.