Body Clock and Brain Control of Blood Pressure

The rostral ventrolateral medulla (RVLM) is a key brainstem region involved in regulating sympathetic nerve activity and BP control. Pre-sympathetic neurons of the RVLM activate sympathetic preganglionic neurons in the spinal cord which then regulate sympathetic outflow to peripheral organs (Fig. 1) [13, 18]. An increase in RVLM neuronal activity leads to an increase in sympathetic nerve activity and thereby causes vasoconstriction, increased heart rate, and increased BP. On the other hand, inhibition of RVLM neurons causes mild hypotension, which emphasizes their role in maintaining basal sympathetic tone [19].

The RVLM integrates information from multiple upstream autonomic and cardiovascular control centers, including the paraventricular nucleus (PVN), nucleus tractus solitarius (NTS), and caudal ventrolateral medulla (CVLM) (Fig. 1) [13, 20]. These regions send signals to the RVLM related to baroreceptor activity, chemoreception and stress responses. Studies show that RVLM neurons have distinct neuronal populations that respond to different afferent inputs and project to specific targets [19, 21]. This network allows the RVLM to coordinate regional sympathetic outflow as well as fine tune cardiovascular function in response to changes in physiological conditions.

The NTS is the primary site in the brainstem that processes cardiovascular sensory input. The NTS directly receives signals from arterial baroreceptors through the glossopharyngeal and vagus nerves [20, 22]. When BP rises, increased baroreceptor activity stimulates NTS neurons, which ultimately inhibit RVLM pre-sympathetic neurons. This results in a decrease in sympathetic outflow to the vasculature and lowers BP which helps to maintain cardiovascular homeostasis [20]. Similar to the RVLM, the NTS also has distinct neuronal populations that contribute differently to cardiovascular regulation depending on their downstream targets [20]. These findings demonstrate that the NTS functions as an integrative center that helps coordinate multiple cardiovascular pathways. Additionally, studies have demonstrated time-of-day differences in neuronal activity and glutamatergic signaling within the NTS which may contribute to circadian regulation of BP [23].

The PVN is a major autonomic center involved in regulating sympathetic outflow, neuroendocrine signaling, and BP [13, 15, 16, 19, 24]. Parvocellular neurons of the PVN project to the RVLM and spinal sympathetic preganglionic neurons to cause an increase in sympathetic nerve activity and contribute to cardiovascular regulation (Fig. 1). Increased activity of PVN neurons has been linked to several forms of experimental hypertension, including salt-sensitive, stress-induced, and renovascular hypertension [25–29].

In addition to its role in autonomic regulation, the PVN also plays a role in fluid and electrolyte homeostasis by producing vasopressin and oxytocin. Through connections to circumventricular organs and other autonomic nuclei, the PVN integrates information regarding circulating hormones, osmotic status, and cardiovascular function. The PVN also receives projections from the SCN, which allows circadian signals to have an influence on both autonomic and neuroendocrine pathways involved in BP regulation [13, 24]. As a result, the PVN is well positioned to coordinate circadian, hormonal, and cardiovascular signals that contribute to daily rhythms in BP.

The dorsomedial hypothalamus (DMH) is important in regulating the activity of the sympathetic nervous system and has been implicated in the control of stress responses, metabolism, and cardiovascular function [30]. DMH neurons project to the RVLM and other autonomic brain regions, and activation of these neurons causes an increase in sympathetic nerve activity, heart rate, and BP [30, 31]. The DMH also receives input from the SCN and exhibits circadian rhythms in neuronal activity which suggest that it may transmit circadian signals to connecting autonomic circuits [32, 33]. Although the DMH is well positioned to control circadian rhythms in sympathetic activity and BP, the specific neural pathways have yet to be clearly established.

The subfornical organ (SFO) is a circumventricular organ that lies outside the blood-brain barrier and can therefore detect circulating hormones and other humoral signals, including angiotensin II and changes in osmolality [13]. Through projections to the PVN and other hypothalamic nuclei, the SFO influences both sympathetic activity and vasopressin release. Importantly, as a major site of central angiotensin II signaling in the brain, the SFO provides an important link between the renin-angiotensin system (RAS) and neural regulation of BP [13, 34].

The supraoptic nucleus (SON) is a major center for vasopressin and oxytocin production in the hypothalamus [24]. SON neurons respond to changes in osmotic status and receive input from other forebrain regions involved in fluid balance regulation. Because vasopressin secretion exhibits daily rhythms and contributes to fluid homeostasis and vascular function, it is likely that the SON plays a role in circadian regulation of BP [13, 24, 35, 36].

The autonomic nervous system (ANS) is a central regulator of blood pressure. The ANS is composed of two arms, the sympathetic and parasympathetic nervous system. Activation of the sympathetic nervous system increases heart rate, vascular resistance, and renin release, whereas activation of the parasympathetic arm slows heart rate. To assess autonomic nerve activity, indirect measurements are made such as heart rate variability (HRV), blood pressure variability (BPV), baroreflex sensitivity (BRS), and circulating catecholamines. HRV analysis measures the variation in time between heart beats. Activation of the sympathetic system lowers HRV, and activation of the parasympathetic system increases HRV. Thus, this analysis gives us insight into the balance between the two arms of the ANS. These measurements allow us to see how changes in autonomic balance across the day contribute to circadian regulation of BP.

The sympathetic nervous system exhibits robust circadian variation activity, with higher activity during the active phase and lower activity during the rest phase [11, 37]. These rhythms play a significant role in daily BP rhythms. In humans, HRV analyses indicate a greater influence of the sympathetic arm during waking hours while the parasympathetic arm is more active during sleep, consistent with the normal pattern of daytime BP elevation and nocturnal dipping [11, 38].

Experimental studies show that both environmental and behavioral cues can modify autonomic rhythms. In a study by Hou et al., changing the time of feeding in global Bmal1 knockout mice shifted the timing of sympathetic activity and BP rhythms [11, 39]. This demonstrates that peripheral cues interact with circadian timing mechanisms to influence cardiovascular regulation [11]. This highlights the importance sympathetic nervous system rhythms in coordinating daily changes in BP and raises the possibility that circadian disruption contributes to abnormal cardiovascular regulation.

The morning blood pressure surge (MBPS) is a critical period in which there is an increased risk of cardiovascular events. During these hours, there are increased incidences of myocardial infarction, sudden cardiac death, and stroke [40–44]. This surge results from multiple physiological processes, such as circadian driven increases in sympathetic activity, catecholamine and cortisol release, and behavioral changes such as awakening, postural shifts, and physical activity [40, 41, 45, 46].

Environmental and behavioral factors can further increase MBPS. For example, being in a cold environment in the morning increases sympathetic activity and BP in healthy adults, suggesting that ambient temperature influences the magnitude of the surge [41]. On the other hand, when circadian rhythms are misaligned due to changes in sleep timing or jet lag, there is an exaggerated MBPS. This is due to disturbances of autonomic balance and behavioral timing [47].

One of the key contributors to MBPS is the postural change from supine to upright position after waking up. This shift causes a gravitational pooling of blood, activation of baroreflex pathways, and compensatory increases in sympathetic outflow and heart rate. When there are abnormalities in baroreflex function or sympathetic reactivity, there is a greater increase in BP [38, 48]. Consistent with this, hypertensive individuals with heightened MBPS show reduced baroreflex sensitivity and altered autonomic balance, providing evidence for their role in excessive morning BP elevation [38]. These findings show that the morning surge in BP is sensitive to both environmental and circadian influences.

Baroreflex sensitivity (BRS) is defined as the change in heart rate or sympathetic activity in response to a given change in BP. This reflex is important for buffering the short-term fluctuations in BP and for maintaining cardiovascular stability. BRS shows a clear circadian rhythm and plays an important role in regulating BP throughout the day [22, 49, 50]. In healthy individuals, BRS is higher during the inactive phase and lower during the active phase which inversely correlates with the typical rhythms of BP. When BRS is reduced during the active phase, it contributes to increases in BP levels and BP variability [49].

In a study by Visniauskas et al., angiotensin II (AngII)-induced hypertension in mice caused disruption of both BP rhythms and baroreflex activity [50]. They observed a blunting of normal daily rhythms in BP, heart rate, and activity, as well as a sex-specific reduction of baroreflex function. Only male mice exhibited reduced BRS in response to AngII [50]. These findings suggest that hypertension not only increases BP but also disrupts the normal circadian rhythms of autonomic reflexes which help stabilize cardiovascular function.

Circadian disruption itself also impairs baroreflex processing [4, 12]. Repeated 6-hour phase advances in light for 22 days reduce glutamatergic signaling within the NTS and decrease expression of glutamate receptor subunits [4]. These responses lead to an increase in BP and support the concept that circadian misalignment reduces BRS [4]. Additionally, peripheral modulators of baroreflex function also show circadian and sex-dependent effects. Natriuretic peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) enhance BRS in a sex-dependent manner. In females, there is a stronger effect that is likely due to a higher expression of natriuretic peptide receptors in the baroreceptor afferent pathways and brainstem nuclei [22]. These sex differences may contribute to variability in circadian BP regulation across sexes.

The RVLM expresses core clock genes, including BMAL1, CLOCK, PER, and CRY, and exhibits circadian variation in neuronal activity that aligns with daily BP rhythms [14].

The NTS shows circadian variation in glutamatergic signaling which contributes to the daily regulation of autonomic function and baroreflex activity [23]. Under normal conditions, glutamatergic synaptic transmission within the NTS changes throughout the circadian cycle. This suggests that excitatory processing in the NTS is under the control of the circadian clock [23]. Buijs et al. provided evidence that the SCN receives direct input from the NTS, enabling it to respond to changes in BP. This suggests a feedback mechanism for BP regulation that is linked to the central circadian clock [51]. Together, these findings suggest that circadian disruption could impact processing of baroreceptor input, although whether glutamatergic signaling contributes to hypertension remains unclear.

The PVN also expresses clock genes and exhibits circadian rhythms in neuronal activity [13, 24]. Because the PVN receives direct input from the SCN, both central circadian signals and local molecular clocks likely play a significant role in the diurnal variation of PVN output. However, the specific clock components in pre-sympathetic neuron populations of the PVN remain unclear. Further studies are needed to define how local clock mechanisms within the PVN shape daily rhythms in BP regulation.

Clock genes regulate neuronal excitability by controlling the transcription of ion channels. BMAL1 regulates the expression patterns of voltage-gated sodium, potassium, and calcium channels which helps control daily rhythms in neuronal excitability within the SCN [8]. Beyond the SCN, circadian mechanisms that regulate electrophysiological properties have been observed across multiple brain regions [52]. This highlights a conserved role of the molecular clock in regulating neuronal function [52]. However, less is known about whether similar clock dependent mechanisms directly contribute to the regulation of autonomic circuits involved in BP regulation. Given that the RVLM, PVN, and NTS all express core circadian clock genes, local regulation of ion channel expression could generate time-of-day differences in neuronal excitability and sympathetic output. However, direct experimental evidence linking molecular clock function to intrinsic excitability within these regions remain limited.

Neuroinflammation within autonomic brain regions has recently been recognized as a factor in the development of hypertension, and emerging evidence indicates that the related inflammatory signaling is regulated in a circadian manner [14, 24]. Microglia exhibit intrinsic circadian rhythms in gene expression, morphology, and cytokine release, which helps to maintain diurnal variation in immune surveillance and inflammatory tone [53–55].

Recent evidence has revealed that clock dysfunction in immune cells within the RVLM may contribute to circadian BP disruption in hypertension [14]. In a Sprague Dawley rat model of stress-induced hypertension by repeated electric foot shock and noise exposure, Zhang et al. showed that RVLM microglia have increased expression of the microglia proinflammatory activation marker, CD86 during the active phase, and dampened CLOCK rhythms [14]. This led to a loss of normal cytokine rhythmicity and a sustained pro-inflammatory state, indicated by an elevation in TNF-α and IL-1β [14]. This was in parallel with increased oxidative stress, impaired sirtuin 1 (SIRT1) signaling, and activation of high mobility group box-1 (HMGB1)-mediated inflammatory pathways. After restoring microglial clock function using SIRT1-enriched extracellular vesicles, they were able to normalize circadian gene expression, cytokine rhythms, and reversed the non-dipping phenotype [14]. These findings support a causal role of microglial clock dysfunction in RVLM-driven sympathetic overactivity and indicates that reprogramming local clock machinery can reverse hypertensive phenotypes [14].

Microglial activation is regulated by extracellular signaling pathways that also exhibit circadian variation. Under control physiological conditions, microglia maintain a homeostatic phenotype during the rest phase [14]. However, circadian disruption or chronic stress shifted microglial toward a pro-inflammatory state [14]. Activation of microglia increases autonomic output by increasing glutamatergic transmission and reducing inhibitory signals within sympathetic control centers [14]. One pathway that may contribute to this response is purinergic signaling through microglial P2 × 7 receptors. Extracellular ATP activates P2 × 7 receptors to promote microglial inflammatory signaling [24]. Because extracellular ATP levels in key circadian regions, such as the SCN, also exhibit daily variation, purinergic signaling might provide a link between circadian timing and neuroimmune activation, but this has yet to be fully established [24]. Together, these pathways suggest that microglia act as an interface between circadian timing mechanisms and neuroinflammatory control of sympathetic activity.

Chronotherapy is where antihypertensive medications are given in a timely manner to align with biological rhythms to improve efficacy and/or reduce dosing [7, 56]. The potential clinical application for chronotherapy for hypertension has been reviewed extensively by Bowles et al., (2018) who highlighted the importance of considering both daytime and nighttime BP regulation when determining medication timing. The circadian regulation of BP, combined with the increased cardiovascular risk associated with nocturnal hypertension, provides a strong rationale for chronotherapy to optimize BP control. Early clinical studies have suggested that taking medications before bed may improve nocturnal BP control and reduce cardiovascular disease risk [57–59]. However, these findings were not confirmed in larger randomized trials such as the TIME study where they found no significant difference between morning and evening dosing on cardiovascular outcomes [60]. These conflicting results suggest that there isn’t a single optimal time for all patients. Instead, treatment may need to be more personalized based on factors such as medication class, BP dipping status, and circadian characteristics.

Individual chronotypes have recently been emerging as a consideration in timing of medication intake. Chronotypes describe an individual’s natural sleep and wake time (commonly referred to as “early birds” or “night owls”). Recent studies analyzing the TIME study have shown that chronotype changes the relationship between medication timing and cardiovascular outcomes [61, 62]. Specifically, later chronotypes appeared to have more favorable cardiovascular outcomes when antihypertensive medications were taken in the evening, whereas earlier chronotypes appeared to benefit more from morning dosing [61, 62]. These findings support a shift towards more personalized chronotherapy [61]. Importantly, these findings do not establish a universal recommendation for timing of medication. Rather, they suggest that timing of medication may be considered in relation to an individual’s sleep-wake pattern and BP profile. This approach aims to consider antihypertensive treatment timing in relation to an individual’s sleep-wake pattern and BP rhythm characteristics, rather than relying only on fixed clock times.

An important consideration is that chronotype and socially imposed sleep timing are not always aligned. For example, a person with a late chronotype who needs to wake up early for work may experience a mismatch between their preferred biological timing and their required sleep-wake schedule. In such cases, clock time alone may not accurately reflect circadian phase. As such, medication timing based solely on a fixed bedtime would not be optimal. This highlights the need for studies that integrate chronotype, habitual sleep timing, occupational/social schedules, and individual BP rhythms when determining optimal timing of antihypertensive therapy. At present, chronotype-based dosing remains an emerging approach rather than a universal clinical recommendation.

Renal denervation (RDx) uses a catheter to ablate renal sympathetic nerves and is an approved therapy for resistant hypertension [63]. This method directly reduces sympathetic signaling to and from the kidney. Clinical trials have shown that RDx causes a sustained reduction in overall BP, which supports the idea that renal sympathetic nerves are important in the development and maintenance of hypertension. In addition to reducing overall BP, there has been recent clinical evidence suggesting that renal denervation may also improve disrupted BP rhythms [64]. Some reports have shown improvements in nocturnal BP, restoration of dipping status, and reductions in MBPS following RDx [65]. However, other studies found little to no effect on circadian BP rhythms despite reductions in overall BP [65]. Together, these findings suggest that sympathetic overactivity may contribute to disruptions in BP rhythmicity, but the effects of RDx on circadian BP regulation are not completely understood.

Preclinical studies have provided mechanistic insight into how renal sympathetic nerves may influence circadian BP regulation. In a rat model of metabolic syndrome, renal denervation normalized blood pressure rhythms and improved cardiovascular injury [66]. Similarly, renal denervation reduced BP and improved BP variation particularly in the rest phase in the spontaneously hypertensive rat [64]. These improvements were accompanied by reduced norepinephrine levels, normalization of RAS rhythmicity, and restoration of circadian gene expression in the kidney [64]. These findings suggest that renal sympathetic signaling contributes not only to increased BP, but also to the loss of BP rhythmicity in hypertension. The mechanisms underlying the effects of sympathetic nerve activity on BP likely involve both reduced sympathetic signaling to the kidney, and changes in afferent feedback to central autonomic circuits. These factors together may help to re-establish the coordination of the peripheral and central circadian clocks. While these findings are promising, further clinical studies are needed to determine whether renal denervation has specific effects on BP rhythmicity in humans.

Neuromodulation represents another potential therapeutic approach. Baroreflex activation therapy (BAT), which electrically stimulates the carotid sinus baroreceptors, can reduce sympathetic activity and lower BP in patients with resistant hypertension [67]. BAT may also influence BP rhythmicity. In a study of patients with resistant hypertension and impaired nocturnal dipping, increasing BAT stimulation specifically during the nighttime increased systolic BP dipping and improved overall dipping patterns [68]. However, in this study, 24-hour, daytime, and nighttime BP did not significantly change [68]. These findings suggest that autonomic neuromodulation may influence BP rhythmicity in addition to lowering mean BP.

Non-invasive approaches to modulate autonomic pathways include transcutaneous auricular or vagal stimulation. These methods have shown modest reductions in BP and heart rate in clinical studies, but substantial heterogeneity still exists among these studies [69]. A recent sham-controlled trial was designed to directly test transcutaneous autonomic neuromodulation in patients with uncontrolled hypertension where they measured BPV, 24-hour BP, HRV, sleep, and autonomic function [70]. Thus, non-invasive neuromodulation is an emerging therapeutic avenue that may be partially relevant to hypertension characterized by excessive sympathetic activity. However, whether these approaches can specifically restore disrupted circadian BP rhythms, and whether their effects depend on the timing of stimulation, remains unknown. Future studies should therefore examine whether neuromodulation targeted to specific circadian phases can improve nocturnal BP, restore normal dipping, or reduce exaggerated MBPS.

Ambulatory blood pressure monitoring (ABPM) is one of the primary clinical tools for assessing 24-hour BP rhythms [71]. In contrast to in office measurements, ABPM has the diagnostic advantage of providing a more reliable assessment of nocturnal hypertension and exaggerated morning surge in BP [3]. Because these phenotypes likely reflect changes in autonomic regulation, baroreflex function, and circadian timing mechanisms, ABPM has the potential to link experimental studies of neurocircadian BP control with clinical hypertension.

The use of ABPM also allows for circadian phenotyping that can help identify high-risk BP patterns even before sustained hypertension develops. For example, disrupted BP rhythms and exaggerated MBPS have been shown to predict future hypertension in individuals with normal but elevated BP [3, 6, 72]. Similarly, elevated MBPS has been associated with an increased risk of arrhythmias, which highlights its broader cardiovascular relevance [40]. Another benefit of using ABPM is the ability to evaluate the influence of behavioral and environmental factors on BP. A recent study by Theodorakopoulou et al. showed that treatment timing in hemodialysis patients altered BP rhythms [73]. When dialysis was performed in the evening, there were more favorable dipping patterns and reduced morning surge compared to when dialysis was completed in the morning. These findings reinforce the importance of timing of treatment. Home dialysis also offers an opportunity to individualize treatment timing, however studies examining the effects on BP rhythmicity remain limited.

Although circadian disruption is strongly associated with hypertension, a clear causal relationship has not been completely defined [2]. In brief, epidemiological studies have consistently linked shift work, social jetlag, and sleep disorders with an increased risk of developing hypertension. Similarly, animal models of circadian disruption indicate increases in BP and loss of normal BP rhythmicity [12, 47]. However, key mechanistic and translational questions remain unclear.

A central issue is whether circadian disruption is a primary driver of hypertension or instead acts to exacerbate pre-existing susceptibility. Longitudinal studies with early circadian stress exposure through the development of hypertension are still needed to determine causality. It is also unclear how circadian disruption interacts with established risk factors such as diet, stress, and genetic predisposition. Although Bmal1 knockout models demonstrate that disruption of the endogenous molecular clock disrupts cardiovascular responses to circadian stress and dietary challenges [9–12], it is still unclear on how the interaction of these pathways may increase the risk of hypertension in otherwise healthy individuals. Defining these interactions will be important for understanding why only a subset of individuals exposed to circadian disruption develop sustained hypertension.

Mechanistically, the relative contribution of central versus peripheral clocks is still not known. Although there is evidence that both SCN driven neural pathways and peripheral clocks in the kidney, vasculature, and adrenal glands are important for BP regulation, it is unclear whether these specific tissue clocks individually could be primary drivers of hypertension or if their misalignment combines to increase risk.

Finally, it remains unclear whether restoring circadian alignment can reverse or improve hypertension in a clinical setting. Animal studies show that restoration of microglial clock function in the RVLM reverses hypertension [14]. Furthermore, restricting feeding to the optimal time of day re-establishes circadian rhythmicity in a range of models such as in mouse studies of diet-induced obesity [74]. However, it is currently unknown whether broader interventions such as light therapy, sleep scheduling, or time restricted eating can meaningfully restore BP rhythms in hypertensive patients.

Recent findings show sex differences in circadian blood pressure regulation, autonomic control, and responses to circadian disruption. However, the underlying mechanisms are not well defined [12, 22, 37, 50]. These studies suggest that males and females may have distinct neuro-circadian pathways that contribute to the development of hypertension. Sex differences are also evident in baroreflex and neurohumoral regulation. Natriuretic peptides have a greater effect on BRS in females, and this is associated with an increase in receptor expression in the afferent pathways and brainstem nuclei [22]. This may contribute to reduced hypertension risk in premenopausal females compared with males.

In terms of autonomic function, preclinical models of hypertension have also shown sex-dependent mechanisms extend to circadian profiles. Thus far, these studies often show an attenuated impact on physiological endpoints in females compared to males. Interestingly, angiotensin II-induced hypertension disrupts circadian rhythms in both sexes but produces distinct physiological consequences such as altered heart rate and activity rhythms in females, and reduced BRS in males [50]. Similarly, when circadian stress is combined with a high-fat diet in a Bmal1 KO rat model, males show greater BP elevation and a disruption of sodium homeostasis compared to females [12].

Circadian disruption studies also indicate sex differences in autonomic responses. In a study by Prabhat et al., dim light at night caused a loss of BP rhythms in both sexes [37]. However, this loss of amplitude was due to lower BP at night in females but higher BP in males during the day. This aligns with observed differences in autonomic function where females had reduced nocturnal sympathetic activity and males had increased daytime sympathetic activity [37]. Of note, time-restricted feeding was shown to normalize these changes suggesting that dietary interventions may be a therapeutic strategy to reduce the adverse effects of dim light at night.

Together, these studies suggest that sex has an influence on both the vulnerability to circadian disruption and the downstream expression of autonomic and cardiovascular phenotypes. Some of the key mechanistic questions that remain include the role of sex hormones in modulating clock gene function within autonomic nuclei, sex differences in SCN output signaling, and whether males and females differ in susceptibility to specific forms of circadian disruption. These gaps have important implications for studying whether chronotherapies may be sex specific.

This article does not contain any studies with human, or animal subjects performed by any of the authors.

The authors declare no competing interests.

No datasets were generated or analysed during the current study.