Sleep Deprivation,Endothelial Dysfunction and Hypertension: A Narrative Review

Abstract

This narrative review aims to elucidate the effects of sleep deprivation (SD) on vascular endothelial cells and blood pressure, synthesize the mechanistic pathways involved, and propose potential intervention strategies, thereby positioning SD as a treatable target in hypertension management. A comprehensive literature search was conducted using databases including PubMed, Web of Science, Embase, and Medline for studies published up to October 2025. Evidence was systematically reviewed to examine SD-induced endothelial dysfunction and its role in blood pressure regulation. Both acute SD (including single-night total sleep < 7 hours, extended wakefulness up to ~36 hours, or ≤5 consecutive nights of restricted sleep) and chronic SD (persistent sleep restriction > 1 week) could induce measurable endothelial impairment and sustained blood pressure elevation. Key mechanistic pathways identified included: (1) vasomotor imbalance, (2) sympathetic nervous system hyperactivation with impaired baroreflex sensitivity, (3) systemic inflammation, (4) oxidative stress, (5) metabolic disturbances, and (6) circadian misalignment affecting vascular clock genes. SD is a significant, modifiable risk factor for endothelial dysfunction and hypertension. These findings highlight the therapeutic potential of endothelial-focused approaches and SD intervention in sleep-compromised populations. Future research should prioritize elucidating the underlying mechanisms and developing valid, cost-effective interventions.

Keywords

sleep deprivation vascular endothelial cells hypertension circadian rhythm genes active interventions

Introduction

For adults, the recommended sleep duration was 7 to 9 hours.¹ Sleep deprivation (SD) referred to a decrease in sleep or a severe lack of sleep resulting from various factors.² SD occurred when a person was not able to obtain sufficient sleep, defined as sleeping less than the duration recommended for health benefits.³ SD was now a recognized health problem in this modern era, which was one of the major causes of visits to the sleep clinics as well.⁴ Thirty-five percent of adults in the United States reported sleeping ≤7 hours during a typical 24-hour day.⁵ It was estimated that 50 to 70 million Americans chronically suffered from a disorder of sleep and wakefulness, hindering daily functioning and adversely affecting health and longevity.⁶

Short sleep duration was confirmed to be a risk factor for hypertension.^7
-9 In clinical settings, ambulatory blood pressure monitoring (ABPM) parameters such as BP variability and nocturnal BP patterns provided important insights into cardiovascular risk and hypertension-related outcomes.¹⁰ SD was capable of triggering different biological effects, such as neural autonomic control changes,¹¹ increased oxidative stress,¹² altered inflammatory¹³ and coagulation responses,¹⁴ and accelerated atherosclerosis,¹⁵ as well as hypertension.¹⁶ Meanwhile, SD was also reported to induce endothelial dysfunction.¹⁷ For example, signal peptide-CUB-EGF domain-containing protein 1 (SCUBE-1), a biomarker associated with endothelial activation, was reported to be significantly elevated in hypertensive patients, particularly in those with hypertension-mediated organ damage, suggesting its potential role as an indicator of vascular injury.¹⁸ However, the mechanisms by which SD affected endothelial cells (ECs) and led to hypertension were not clear, the present narrative review considered these points.

Literature Search

To support the synthesis of current evidence on the relationship between SD, endothelial dysfunction, and BP regulation, we conducted a structured literature search in PubMed, Web of Science, Embase, and MEDLINE, covering studies published up to October 2025. The search combined relevant MeSH terms and keywords, including “sleep deprivation,” “insufficient sleep,” “inadequate sleep,” “sleep loss,” “sleep insufficiency,” “sleep fragmentation,” “sleep debt,” “lack of sleep,” “not have enough sleep,” “endothelial*,” “vascular*,” “endothelial dysfunction,” “hypertension,” and “blood pressure.” Inclusion criteria were as follows: (1) peer-reviewed studies published in English, (2) studies investigating the mechanisms linking SD to endothelial function and/or BP regulation, and (3) both human and animal studies, as well as mechanistic reviews that provided insights into physiological pathways. Studies were screened at the title and abstract level, followed by full-text review for eligibility. Reference lists of selected articles were also manually searched to identify additional relevant publications not captured in the initial search. This review was conducted as a narrative review rather than a systematic review. Therefore, the selection of studies was primarily based on their relevance to the mechanisms linking SD, endothelial dysfunction, and BP regulation. Studies were selected to provide representative evidence across experimental, translational, and clinical research. Both human and animal studies were included to offer complementary mechanistic and clinical perspectives.

Mechanisms of Vasodilation-Contraction Imbalance Induced by Sleep Deprivation

Direct Effects on Contractile and Relaxation Imbalance of Endothelial Cells: Endothelin-1/Nitric Oxide (ET-1/NO)

The most intuitive manifestation of vascular endothelial dysfunction was the abnormal regulation of vascular tone.¹⁹ The endothelium-derived constricting and relaxing factors jointly maintained the balance of vascular tone, thereby regulating BP.²⁰ The vasoconstrictor factors were ET-1, angiotensin II, thromboxane A2, thrombin, superoxide anion, and others. The vasodilative molecules included NO, prostaglandin I2,²¹ endothelium-derived hyperpolarizing factor (Figure 1).²²

Figure 1.

Possible mechanisms by which sleep deprivation (SD) impairs endothelial function and contributes to hypertension. SD induces sympathetic activation, oxidative stress, inflammation, circadian disruption, metabolic disturbances, and appetite changes, which collectively impair endothelial NO production by reducing eNOS expression (through decreased BH₄, increased ADMA, and reduced DDAH), limiting substrate availability (L-arginine) and promoting eNOS uncoupling. Meanwhile, ET-1 expression is also increased. These alterations contribute to vascular dysfunction and hypertension.

ET-1 was an effective vasoconstrictive peptide, which played an important role in endothelial vasoconstriction.²³ After arterial perfusion with BQ-123 (a selective ET-A receptor antagonist) in the forearm blood flow of elder normotensive participants, the vasodilatory response of individuals who were short sleepers (6.1 ± 0.1 h/night) was 2.5 times (20% vs 8%, P < .05) higher than that of normal sleep group (7.6 ± 0.1 h/night), suggesting increased ET-1 activity during SD.²⁴ Using radioimmunoassay, 1 study found that plasma ET-1/2 levels in male Wistar rats increased significantly after 96-hour SD (6.58 fmol/mL) compared with controls (5.07 fmol/mL, P < .03) and the 24-hour SD group (~5.20 fmol/mL, P < .04), whereas 24-hour SD did not significantly alter ET-1/2 levels, suggesting that prolonged SD may be required to elevate plasma ET-1/2 levels.²⁵

There were 2 pathways²⁶ by which NO was produced in ECs, including endothelial NO synthase (eNOS) pathway and eNOS-independent pathway (nitrite could be either catalyzed to NO by oral facultative anaerobic bacteria and acidic gastric juice, or reduced by numerous proteins and enzymes in plasma such as hemeproteins, xanthine oxidoreductase, aldehyde oxidase and mitochondrial enzymes).²⁷ NO produced from L-arginine by the first pathway (eNOS pathway) was the primary source of blood NO.²⁶ The expression of eNOS in male Sprague–Dawley (6-8 weeks old) rats was reduced after suffering from 72-hour SD of rapid eye movement by using the inverted flowerpot technique—a well-established method in which animals are housed on small platforms surrounded by water, where the loss of muscle tone during rapid eye movement sleep causes them to fall and wake.²⁸ The decrease in NO inhibited sleep (non-rapid eye movement and rapid eye movement sleep) in rats.^29,30 The vicious cycle of NO reduction and SD might contribute to the development of hypertension. In a study composed of hypertensive middle-aged and older adults, there was reduced acetylcholine-NO-mediated endothelium-dependent vasodilation and bradykinin-induced endothelial tissue plasminogen activator release in insufficient sleep group (5.8 ± 0.1 h/night) compared with the control group (7.6 ± 0.1 h/night).³¹ In this study, the changes of endothelium-dependent vasodilation were mediated primarily by acetylcholine but not by bradykinin and nitroprusside, suggesting that sleep loss-induced hypertension may not involve impaired endothelium-dependent hyperpolarization as its underlying mechanism.³¹ Bain et al. found that after injecting acetylcholine into the forearm artery of the elder normotensive male participants, the response to acetylcholine in individuals with short sleep (6.1 ± 0.2 h/night) was significantly diminished (4.6 ± 0.3 to 11.7 ± 1.0 vs 4.4 ± 0.3 to 14.5 ± 0.5 mL/100 mL tissue/min, ~20%, P < .05) compared with controls (7.7 ± 0.2 h/night).³² Next, all the subjects were infused with the vasodilator inhibitor—N-monomethyl-L-arginine (a broad NO synthase inhibitor), but it only attenuated the response to acetylcholine of the control group (~40%). Therefore, the loss of endothelium-dependent vasodilation in SD group might be related to reduced NO bioavailability.³² Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NOS, which inhibits the synthesis of NO.³³ It was an independent predictor of cardiovascular mortality and morbidity.³⁴ Słomko et al³⁵ found that after experiencing 24-hour SD, 40 healthy male subjects (mean age: 31.2 ± 6.3 years; body mass index: 24.6 ± 2.6 kg/m²) exhibited a significant decrease in plasma L-arginine (68.8 ± 10.2 vs 78.2 ± 12.9, P = .001) compared with baseline along with an increase in ADMA (0.4 ± 0.1 vs 0.3 ± 0.1, P = .004), reflecting the disturbance of NO production of vascular ECs. Meanwhile, BP, especially systolic BP, remained elevated throughout the whole process.³⁵ These results provided potential mechanistic links between SD, impaired NO bioavailability, and elevated BP in humans. A study assessing sleep quality in patients with diabetes using the Pittsburgh Sleep Quality Index³⁶ classified those with an overall score > 5 as “poor sleepers.” The ratio of serum L-arginine/ADMA was decreased in poor sleepers compared with the good sleep group (35.1 [27.8-41.1] vs 42.0 [31.4-54.3], P < .01). The whole score was positively associated with the level of ADMA (r = .39, P < .01) and negatively with L-arginine/ADMA (r = −.28, P = .02). Notably, pure sleep duration was not significantly associated with either indicator (P > .05).³⁶ Hence, sleep quality, more than duration, appeared critical for L-arginine/ADMA/NO balance. Dimethylarginine dimethylaminohydrolase (DDAH) including DDAH1 and DDAH2, can catalyze the decomposition of ADMA, thereby regulating eNOS function and local NO concentration.^37,38 It was beneficial to improve the progression of hypertension.³⁹ Meanwhile, increasing the cerebral level of DDAH not ADMA was proved to improve insomnia, which was regulated in part by oxidative stress.^40,41 In basic research, Jiang et al⁴² found that SD (5 days) could cause NO-induced endothelial dysfunction and an increase in BP (systolic BP: ↑16%; diastolic BP: ↑18%) in male middle-aged (24 weeks old) Sprague-Dawley rats by damaging the eNOS/NO/cyclic guanosine monophosphate pathway. SD was associated with decreased eNOS phosphorylation and reduced NO and cyclic guanosine monophosphate content in ECs of adult rats, but not in young (6-week-old) rats.⁴² This finding was in line with the concept that vascular ECs are more vulnerable to damage with aging,⁴³ and that this damage might be amplified by SD.

Most mechanistic evidence was derived from animal models. Human studies remained largely observational, relying on functional or biomarker surrogates rather than direct molecular interrogation of the upstream regulatory mechanisms or downstream signaling cascades linking SD to endothelial dysfunction. Finally, whether SD alone could induce eNOS uncoupling, a mechanism well-documented in obstructive sleep apnea involving peroxynitrite overproduction and reduced tetrahydrobiopterin availability, remained an open question.⁴⁴

Sleep Deprivation Induces Sympathetic Activation

Sleep disorders and insufficiencies were often accompanied by heightened sympathetic activity, a known contributor to increased cardiovascular risk.⁴⁵ Activation of the hypothalamic–pituitary–adrenal axis and heightened sympathetic tone were also reported in the patients with insomnia and hypertension.⁴⁶ Heart rate variability could provide information about functioning of the autonomic nervous system and interaction of sympathetic and parasympathetic (vagal) pathways.⁴⁷ In a male cross-over study, sleep restriction (awake from 3:00 am to 7:00 am) not sleep fragmentization resulted in higher heart rate (P = .018) and lower pNN50 (percentage of RR intervals with >50 ms variation, a marker which reflected vagal activity, P = .012) during sleep stage N1 (non-rapid eye movement stage 1), as well as lower SDNN (standard deviation of RR intervals, a global marker for total heart rate variability, P = .009) during wakefulness compared with baseline.⁴⁸ Compared with non-shift workers, a significantly higher LF/HF (low frequency/high frequency, a marker which reflected sympathovagal balance), lower heart rate variability, and a trend for a lower flow-mediated dilatation (P = .08) were observed among shift workers required to stay awake for 30.5 hours, which reflected higher sympathetic and/or lower parasympathetic activities.⁴⁹ In a study of interventions for all, acute SD (36 hours) increased sympathetic activation, and decreased parasympathetic cardiovascular modulation and spontaneous baroreflex sensitivity in 18 healthy participants compared with baseline.⁵⁰ However, these human studies investigating autonomic responses to SD were conducted in relatively small experimental samples. In another cross-over study,⁵¹ partial SD (3.5-5 hour) for 5 nights significantly increased sympathetic activity of 13 healthy Caucasian subjects compared with normal sleep condition (7-9.5 hour; serum norepinephrine [162 ± 58 vs 119 ± 46 ng/mL, P < .01]). Although the differences in BP rise (systolic BP: 112.9 ± 11.7 vs 108.8 ± 9.8 mmHg; diastolic BP: 65.3 ± 6.9 vs 63.6 ± 4.8 mmHg; P > .05) were not statistically significant, there was a decrease in endothelial-dependent venodilatation (maximal venodilatation [41 ± 20 vs 100% ± 22%, P < .001]) induced by acetylcholine.⁵¹ Also, the mean dose of phenylephrine required to induce 20% venoconstriction was significantly reduced after SD (332 ± 107 vs 846 ± 189 ng/mL, P < .01).⁵¹ Similarly,⁵² the urinary excretion of norepinephrine was increased in 36 never-treated mild to moderate hypertensive patients suffering from 4-hour SD (awake from 11:00 pm to 3:00 am) compared with when they got enough sleep (2.12 ± .31 vs 1.57 ± .26 mmol/min, P < .05). In the next morning after SD, the BPs (systolic BP: 154.86 ± 5.91 vs 147.72 ± 6.84 mmHg, P < .001; diastolic BP: 96.29 ± 7.25 vs 92.28 ± 7.26 mmHg, P < .01) and heart rate (75.19 ± 6.33 vs 69.73 ± 5.26 beats/min, P < .05) remained elevated.⁵² The divergence reflected differences between healthy individuals and patients with hypertension, suggesting that an intact endothelium in healthy subjects might initially buffer the hemodynamic consequences of sleep loss, whereas this compensatory capacity might be impaired once hypertension develops, rendering BP more susceptible to SD. Besides, the nocturnal BP phenotype of all hypertensive participants became non-dipping when experiencing SD, underscoring the heightened vulnerability of nocturnal BP regulation.⁵² Interestingly, the BP (mean arterial pressure: 133.7 ± 2.8 vs 102.1 ± 3.8 mmHg, P < .05) and heart rate (500.9 ± 4.8 vs 416.5 ± 5.7 bpm, P < .05) were significantly increased in male Sprague–Dawley rats suffering from 21 days of chronic SD (awake for 20 h/day) compared with control rats.⁵³ The effects might be related to the upregulation of angiotensin II type 1 receptors in the nucleus tractus solitarii, contributing to impaired baroreflex sensitivity (pre-SD: −1.16 ± .13 bpm/mmHg vs post-SD: −.46 ± .12 bpm/mmHg, P < .05). Then, microinjection of losartan into the nucleus tractus solitarii reversed this damage of sleep-deprived rats (pre-intervention: −.46 ± 0.12 bpm/mmHg vs post-intervention: −1.01 ± .07 bpm/mmHg, P < .05).⁵³ Nevertheless, whether similar central mechanisms operate in humans exposed to chronic sleep restriction remained to be clarified.

Sleep Deprivation Leads to an Inflammatory Storm

The inflammation induced by sleep loss was attributed to glucocorticoids and catecholamines stimulating the activation of nuclear factor-kappa B to upregulate granulocytes and cytokines.⁵⁴ However, 1 study suggested that 1 week of sleep restriction (sleep from 2:00 to 6:00) directly impaired endothelial function through inflammatory pathways independent of sympathetic activation, and sympathetic activation under long-term SD only aggravated the inflammatory responses.⁵⁵ A recent study¹³ suggested that SD increased brain-derived prostaglandin D2 efflux mediated by ATP-binding cassette transporter 4, which might cross the blood–brain barrier and trigger systemic inflammation. Interleukin-6 and interleukin-17A emerged as the most prominent pro-inflammatory cytokines induced by SD.¹³ Interleukin-17 was mainly secreted by immune cells (T helper cells),⁵⁶ and its subtype interleukin-17A could reduce NO production by phosphorylating threonine 495 of eNOS in porcine aortic ECs. Systemic infusion of interleukin-17A was shown to increase BP in adult male C57BL/6 mice.⁵⁷ However, direct evidence linking interleukin-17-mediated pathways to SD-related hypertension in humans remains limited. Following 5 consecutive nights of partial SD (awake from 23:00 to 03:00), healthy male adults exhibited significantly elevated serum levels of interleukin-17A, interleukin-1β, interleukin-6, and C-reactive protein compared with baseline, along with increased heart rate which persisted until the following 2 nights of recovery sleep (P < .05).⁵⁸ Consistent with this, a recent prospective study in 14 healthy young men⁵⁹ found that 24-hour total SD significantly impaired endothelial function (flow-mediated dilatation: decreased from 6.7% ± 6.8% to 1.7% ± 3.3%, P = .009), accompanied by elevated salivary interleukin-1 (36 ± 21 to 47 ± 24 pg/mL, P = .004) and interleukin-6 (22 ± 7 to 36 ± 11 pg/mL, P = .0005). Notably, the decline in flow-mediated dilatation strongly correlated with the increase in interleukin-1 (r = −.813, P = .001) and interleukin-6 (r = −.735, P = .003), suggesting a direct link between acute inflammation and endothelial dysfunction. In contrast, the level of tumor necrosis factor alpha was reduced and BP remained unchanged throughout the process.⁵⁸ These findings suggested that inflammatory responses to SD may vary across cytokine pathways and experimental conditions. In addition, the BP elevation under SD could aggravate vascular shear stress, which increased the levels of activation markers in ECs (such as E-selectin and intercellular adhesion molecule-1), and activated ECs in turn induced more production of interleukin-6.⁵⁴ In healthy men suffering from 40-hour SD, the elevation of E-selectin level occurred nearly 7 hour before the onset of full sympathetic activation and BP rise, which reflected a greater sensitivity of endothelial dysfunction in the early stages of SD.⁶⁰ Several studies reported an increase in C-reactive protein after SD, both in the long-term sleep-deprived population and in normal sleepers with sudden sleep loss.^61
-63 C-reactive protein was reported to interact with ECs, reduce the expression and bioactivity of eNOS and the production of NO, and increase the release of vasoconstrictors and adhesion molecules.⁶⁴ The role of C-reactive protein between SD and endothelial function was unknown. A meta-analysis showed that sleep disturbance and long sleep duration, but not short sleep duration, were associated with elevated systemic inflammatory markers.⁶⁵ However, most of the included studies were non-prospective and non-objective⁶⁵ studies, so the relationship between short sleep duration and systemic inflammation remains inconclusive. The inflammatory effect might be more obvious with the accumulation of SD and long-term circadian rhythm disorder, and more sensitive inflammatory markers were needed to verify this idea in the future. However, most mechanistic evidence originated from experimental and animal studies, and further clinical investigations were required to clarify the translational relevance of these findings.

Sleep Deprivation Leads to Oxidation/Antioxidation Imbalance

The body produces less reactive oxygen species and free radicals during sleep than during wakefulness.⁶⁶ They could not only directly inhibit the bioactivity of NO, but also stimulate the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B)-mitogen-activated protein kinase (MAPK) pathway related to redox transcription factors, which might lead to overexpression of redox genes and subsequent inhibition of eNOS mRNA expression and its bioactivity.⁶⁷ Antioxidant molecules and enzymes such as reduced glutathione, catalase, glutathione peroxidase, superoxide dismutase, seemed active in sleep, helping to reduce oxidative stress,⁶⁸ but this increase remains controversial.⁶⁹ Compared with the control group, there was a significant decrease in glutathione levels but an increase in thiobarbituric acid reactive substance (an index of lipid oxidation indicating the levels of malondialdehyde in the tissues) levels and catalase activity in the plasma of rapid eye movement sleep-deprived (96 hours) juvenile but not adult male Wistar rats.⁷⁰ Similarly, Nawi et al⁷¹ found that the activity of superoxide dismutase was significantly reduced but malondialdehyde concentrations were increased in male Sprague–Dawley rats of rapid eye movement sleep-deprived (72 hours) compared with control rats. The resulting accumulation of superoxide anion might induce lipid peroxidation, which might contribute to aortic endothelial dysfunction and increased systolic BP. Furthermore, SD was associated with accumulation of reactive oxygen species and consequent oxidative stress, specifically in the gut.¹² The accumulation of reactive oxygen species might lead to upregulation of nuclear factor-kappa B in the gut and potential damage to intestinal barrier function (the levels of 2 critical tight junction proteins in the ileum of SD mice, zonula occludens-1 (ZO-1) and occludin were decreased), probably in turn aggravating systemic inflammation.⁷² However, there was no reliable evidence that the changes of intestinal flora under SD-induced BP elevation.^73,74 Only one intestinal microbial function module—2-aminoethylphosphonate transport system was observed to be simultaneously deficient in both normotensive and hypertensive subjects who slept short (≤6 hours) duration/day.⁷⁴ Sleep-related deoxycholic acid was also found to be upregulated in intestinal fecal metabolites in older people with short sleep duration,⁷⁵ and the deoxycholic acid was proved to attenuate phenylephrine-induced vasoconstriction in arterioles of mice and BP rise in male C57BL/6 specific pathogen-free (SPF) mice.⁷⁶ Nevertheless, current evidence in humans remains limited and further clinical validation is needed.

Hyperlipidemia and Hyperglycemia

SD was closely associated with the prevalence of metabolic syndrome.^77
-79 Metabolic disturbances induced by SD might further exacerbate endothelial dysfunction and contribute to hypertension development. SD not only was associated with hypertension, but also with hyperglycemia (insulin resistance) and dyslipidemia.^80
-86 However, the relationship between SD and dyslipidemia appeared to be complex and might be influenced by oxidative stress and inflammatory pathways.^85,87 The coexistence of hyperglycemia and hyperlipidemia was characterized by activation of the ET-1 system and reduced eNOS and nuclear factor erythroid 2-related factor 2 (Nrf2, an antioxidant factor) activity, which might contribute to endothelial dysfunction.⁸⁸ Kong et al⁸⁹ reported that high-fat/high-glucose conditions could exacerbate the endothelial insulin resistance and dysfunction, accompanied by decreased NO levels, elevated ET-1 levels, weakened PI3K/Akt/eNOS signaling, and impaired endothelium-dependent vasodilation function.⁸⁹ Among hypertensive patients with metabolic syndrome, there was likely a high prevalence of target-organ damage.⁹⁰ Therefore, improving sleep duration and quality represented an important strategy for preventing hypertension and metabolic disorders.

Obesity, Leptin, and Ghrelin

Alterations in appetite-regulating hormones, particularly leptin and ghrelin, were implicated in obesity and metabolic dysregulation, which were closely associated with hypertension.^91,92 In the Wisconsin sleep cohort study, short sleep duration was associated with reduced leptin, elevated ghrelin, and increased body mass index.⁹³ Ghrelin was found to activate AMPK signaling in angiotensin II-induced hypertensive male C57BL/6 mice, leading to inhibition of oxidative stress, increased NO production, improved endothelial function, and reduced BP.⁹⁴ In addition, although chronic not acute hyperleptinemia and leptin resistance were associated with hypertension and endothelial dysfunction, these effects were in part related to obesity and gender.^95
-97 These hormonal disturbances caused by SD might lead to increased caloric intake, particularly from energy-dense foods rich in fat and carbohydrates,⁹⁸ thereby promoting weight gain and metabolic dysregulation. Such a high-calorie diet was shown to promote NO inactivation, ROS production and BP elevation in female Fischer rats.⁹⁹ Furthermore, it was well established that endothelial dysfunction in obesity-associated hypertension was related to NO bioavailability, oxidative stress, sympathetic activation, renin-angiotensin system, insulin resistance, as well as leptin resistance.¹⁰⁰

Circadian Rhythm Gene Variations in Sleep Deprivation-Related Vascular Dysfunction

The circadian rhythm of mammals consisted of a central clock and peripheral clocks. The central clock is located in the suprachiasmatic nucleus, and the peripheral clocks exist in almost every tissue.¹⁰¹ Clock-controlled genes acting on the cardiovascular system could regulate various physiological functions of the circulation, such as endothelial function, BP, heart rate, acute myocardial infarction and the onset of arrhythmia.¹⁰² Circadian rhythms were controlled by clock genes, which formed an oscillatory mechanism that was based on a self-sustaining transcription-translation feedback loop consisting of positive and negative feedbacks (Figure 2).¹⁰³

Figure 2.

The association of circadian rhythm genes with endothelial cells (ECs) and blood pressure (BP). The regulation of circadian rhythms involves both the central circadian clock and peripheral endothelial clocks. At the molecular level, a BMAL/CLOCK–PER/CRY negative feedback loop (mediated by E-box) drives 24-hour oscillations in gene expression. Dysregulation of this loop may disrupt endothelial homeostasis, thereby promoting vascular dysfunction and hypertension.

The reduced time spent sleeping disrupted the circadian time structure.¹⁰⁴ Chronic SD (2 months) resulted in abnormal expression of brain and muscle ARNT-like 1 (BMAL1), circadian locomotor output cycles protein kaput (CLOCK), and cryptochrome 1 (CRY1) in the circadian rhythm-related nuclei of experimental mice.¹⁰⁵ In aortic ring tissue bath studies, the acetylcholine induced 73% ± 1.9% relaxation in wild-type mice but this response was severely blunted to 26.9% ± 1.7% in BMAL1-knockout mice (P < .05). In this process, eNOS was observed to be uncoupled in aorta characterized by reduced levels of tetrahydrobiopterin, elevated dihydrobiopterin levels, reduced tetrahydrobiopterin:dihydrobiopterin ratio, and production of superoxide in place of NO.¹⁰⁶ Naive aortas from BMAL1-knockout and CLOCK mutant mice both exhibited an impaired endothelium-dependent vasodilator response to acetylcholine, but the vasodilation in the latter was also related to the conditions of light-dark and dark-dark.¹⁰⁷ Moreover, the downregulation of endothelium-derived vasodilation in BMAL1-knockout mice was associated with attenuated phosphoinositide dependent kinase/Akt/eNOS signaling.¹⁰⁷ Compared with control group, SD (awake for 20 h/day for 7 days) increased the expression of pro-inflammatory cytokines and adhesion molecules, activated cyclic adenosine monophosphate/protein kinase A/nuclear factor-kappa B and the binding of monocytes to ECs, while reducing the expression of CRY1 in male C57BL/6 mice ECs.¹⁰⁸ However, overexpression of CRY1 in ECs could reverse this vascular inflammation.¹⁰⁸ Okamura et al¹⁰⁹ reported that mice lacking both CRY1 and CRY2 exhibited salt-sensitive hypertension with hyperaldosteronism. In addition, mutation in the period 2 (PER2) gene in mice was associated with aortic endothelial dysfunction involving decreased production of acetylcholine-induced NO and vasodilatory prostaglandins I2, and increased release of cyclooxygenase-1-derived vasoconstrictors.¹¹⁰ Interestingly, BP was reduced in the mutant mice compared with the control group, suggesting that the parasympathetic nerve or acetylcholine-mediated signaling in the heart of the PER2 gene mutant mice remained intact.¹¹⁰ In PER2 mutant mice, there was significantly increased Akt signaling which was associated with increased oxidative stress and reduced eNOS activation, which induced vascular senescence and decrease in NO bioavailability.¹¹¹ It was also reported that global PER2 mutant and BMAL1 mutant mice showed lower BP but the endothelial-specific deletion of BMAL1 did not affect the variation in BP.¹¹² In short, there was no clear evidence on the effect of these circadian genes, which sometimes even manifested a hypotensive phenotype after being completely removed.^113,114 These observations highlighted the intricate role of circadian clock genes in coordinating vascular signaling and BP regulation, with systemic and endothelial circadian mechanisms potentially playing distinct roles.

Interventions to Improve Endothelial Function During Sleep Deprivation

Exercise Training

Continued physical exercise was shown to alleviate impairment of reactive hyperemia in patients with essential hypertension through increased release of NO,^115
-117 although increased physical activity might be offset by the negative consequences of chronically disturbed sleep.¹¹⁸ A meta-analysis revealed that moderate continuous aerobic training (50% PO2max) for 30 to 40 min/session at least 3 times/week, was effective to improve endothelium-dependent vasodilation in hypertensive individuals.¹¹⁹ In healthy young (17-30 years old) adults, completing the aerobic exercise (a single 50-minutes bout of cycling exercise) before acute restricted sleep (3.5 hours) could attenuate the increased 24 hours ambulatory systolic BP but not restore it to baseline, and this BP-lowering effect only occurred in participants identifying as late chronotypes (P = .045).¹²⁰ This finding suggested that exercise may partially offset the vascular effects of acute sleep restriction, although it may not fully normalize BP. It was reported that compared with before training, 7 weeks of a moderate to high-intensity interval training¹²¹ prevented the decrease of acetylcholine-induced vasodilation in healthy young (27.3 ± 5.4 years old) males experiencing 40-hour SD. In the absence of significant changes in BP, pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α, vascular endothelial markers (monocyte chemoattractant protein-1 and E-selectin), and pulse wave velocity seemed to have changed earlier under SD.¹²¹ Fortunately, exercise training improved the endothelial dysfunction of the participants.¹²¹ In addition, compared with the normal sleep and exercise group and the pure normal sleep group, a session of high-intensity interval exercise to expend 500 kcals of energy,¹²² even after acute SD (3-3.5 hours), could still maintain the brachial artery flow-mediated dilatation of the healthy male (31 ± 5 years old) participants. However, moderate-to-vigorous intensity exercise after SD might be detrimental to cardiovascular health. In contrast, the habit of regular exercise might mitigate the adverse effects of SD (Figure 3).¹²³

Figure 3.

The possible options for addressing endothelial dysfunction caused by sleep deprivation (SD).

Noise Reduction

Environmental noise was an important factor contributing to sleep disturbance and SD. Exposure to noise levels of >75 dB over 1 year could result in poor sleep efficiency and short sleep duration.¹²⁴ Nocturnal noise affected not only autonomic regulation (increased heart rate and BP mediated by sympathetic activation and/or parasympathetic withdrawal), but also vascular function through the induction of endothelial dysfunction.¹²⁵ When exposed to 3 nighttime noise scenarios—background noise in home, 30 or 60 train noise events, with average sound pressure levels of 33, 52, and 54 dB, respectively, the flow-mediated dilatation of the brachial artery was gradually decreased in 70 healthy volunteers (11.23% ± 4.68%, 8.71% ± 3.83%, and 8.47% ± 3.73%; P < .001).¹²⁶ Mean sound level of 72 dB applied by loudspeakers for 4 days caused an increase in systolic and mean BP in mice, as well as endothelial dysfunction.¹²⁷ Noise exposure was associated with eNOS uncoupling in ECs, characterized by increased eNOS expression, elevated vascular tyrosine nitration in the endothelial layer, and eNOS S-glutathionylation, ultimately leading to reduced NO levels.¹²⁷ Interestingly, Vitamin C was reported to partially reverse the nocturnal noise-induced reduction in flow-mediated dilatation due to excessive oxidative stress.¹²⁸

Other Protective Measures

Several nutritional, behavioral, and therapeutic strategies were developed to mitigate endothelial dysfunction associated with SD. The supplementation with L-arginine was shown to protect against SD-induced hypertension and endothelial dysfunction (attenuated NO-mediated vasodilation), and upregulated the eNOS/NO/cyclic guanosine monophosphate pathway in middle-aged Sprague–Dawley rats.⁴² It was also reported that flavonoids might improve endothelial function by increasing NO bioavailability, leading to relaxation of the endothelial smooth muscle, thus controlling vascular tone and BP.¹²⁹ In healthy individuals (25.31 ± 3.60 years old) experiencing 1 night of SD, the flavanol-rich group had higher level of flow-mediated dilatation (7.04 ± .62 vs 5.00% ± .49%, P < .001) and lower BPs compared with flavanol-poor group (systolic BP: 116.9 ± 1.6 vs 120.8 ± 1.9 mmHg, P < .001; diastolic BP: 70.5 ± 1.2 vs 72.3 ± 1.2 mmHg, P = .01).¹²⁹ In addition, the melatonin might increase endothelium-dependent vasodilation by inhibiting calcium channels and stimulating eNOS pathways.¹³⁰ However, exposure to nocturnal light could lead to inhibition of melatonin secretion.^131
-133 A cross-sectional study even found that nocturnal light at home was significantly associated with increased nighttime BP in elderly individuals independently of overnight urinary melatonin excretion.¹³⁴ Wearing blue light glasses could block nocturnal light and maintain secretion of melatonin.¹³⁵ However, the benefits of melatonin on BP were debatable.¹³⁶ Two cross-sectional studies also showed that catch-up sleep (sleep 1-2 hours more on weekends than on weekdays) could reduce the risk of hypertension.^137,138 The BP-elevating effect of short sleep duration could be reversible by 6 weeks of increased habitual sleep duration (Figure 3).¹³⁹ Slow-breathing training that stimulated parasympathetic activation was also reported to improve endothelial function and BP, particularly in those without SD.¹⁴⁰ Cognitive behavioral therapy demonstrated significant efficacy in the management of primary insomnia.¹⁴¹ Whether cognitive behavioral therapy is beneficial in improving markers of cardiovascular diseases such as endothelial function in people with insomnia and hypertension, was currently being investigated in clinical trials.¹⁴² A meta-analysis showed that cognitive behavioral therapy could improve systolic BP (−8.67 mmHg, P < .001), diastolic BP (−5.82 mmHg, P < .001), sleep quality and negative mood in patients with hypertension.¹⁴³ SD was regarded as a stressor,¹⁴⁴ and cognitive behavioral therapy could also improve the anxiety and depression symptoms associated with insomnia,¹⁴⁵ which had multiple therapeutic effects. In addition, the most commonly used sedative-hypnotics in insomnia had both endothelium-dependent and endothelium-independent vasodilatory effects,¹⁴⁶ but their impact on endothelial function and BP in sleep‑deprived individuals remained unclear. A recent meta‑analysis of randomized controlled trials indicated that hypnotics did not significantly affect nocturnal or 24-hour BP.¹⁴⁷ Notably, prospective data revealed that the use of benzodiazepines and nonbenzodiazepines was associated with an increased risk of future cardiovascular events.^148,149 The 2017 American Academy of Sleep Medicine clinical practice guidelines for insomnia¹⁵⁰ recommended cognitive‑behavioral therapy for insomnia as first-line treatment, with pharmacologic hypnotics reserved for patients who did not benefit from non-pharmacologic measures, used for limited durations and monitored closely, particularly in those at risk for cardiovascular events. Therefore, although sedative‑hypnotics improved sleep symptoms in selected patients, their routine use to mitigate SD-related endothelial dysfunction or hypertension was not supported by current evidence and should be undertaken with caution.

Conclusions

Based on classical hypertension mechanisms, this review systematically summarized the functional alterations of vascular ECs under SD and proposed potential therapeutic interventions. As the primary vascular barrier, ECs play an important role in BP regulation. Despite their crucial functions, fundamental research investigating the impact of SD and circadian rhythm disruption on vascular ECs and hypertension remains limited. It is worth noting that the current clinical studies on sleep and hypertension also have some shortcomings.¹⁵¹ Future research should further clarify which types of SD (reduced sleep duration, sleep fragmentation, or circadian misalignment) exert the greatest impact on endothelial function and BP regulation. In addition, integrating endothelial biomarkers and ABPM parameters into clinical studies may help better characterize SD-related vascular alterations and identify populations that are particularly vulnerable to SD-induced cardiovascular risks. Moreover, developing effective strategies to mitigate and potentially reverse SD-induced vascular damage represents an important direction for future research.

Footnotes

ORCID iD

Yu Yan

Ethical Considerations

As a narrative review that synthesizes data and conclusions exclusively from publicly available papers, ethical approval is not applicable.

Author Contributions

Yu Yan: Conceptualization, Methodology, Investigation, Writing – original draft, Writing – review & editing. Dan Yang: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. Shuangliang Ma: Conceptualization, Investigation, Writing – original draft, Writing – review & editing. All authors contributed to: (1) substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, and (3) final approval of the version to be published.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Declaration of Generative Artificial Intelligence (AI) and AI-Assisted Technologies

No AI techniques were used for writing.

References

Chunnan

Shaomei

Wannian

The association between sleep and depressive symptoms in US adults: data from the NHANES (2007-2014). Epidemiol Psychiatr Sci. 2022;31:e63.

Yang

Shi

Wang

Kang

Xiu

JZ.

[Molecular mechanism of sleep deprivation-induced body injury and traditional Chinese medicine prevention and treatment: a review]. Zhongguo Zhong Yao Za Zhi. 2023;48(21):5707-5718.

Chaput

McHill

Cox

, et al. The role of insufficient sleep and circadian misalignment in obesity. Nat Rev Endocrinol. 2023;19(2):82-97.

Liew

Aung

Sleep deprivation and its association with diseases- a review. Sleep Med. 2021;77:192-204.

Bandyopadhyay

Sigua

NL.

What is sleep deprivation?

Am J Respir Crit Care Med. 2019;199(6):11-12.

Institute of Medicine Committee on Sleep M, Research. The National Academies Collection: reports funded by National Institutes of Health. In: Colten

Altevogt

eds. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. National Academies Press; 2006.

Haghayegh

Strohmaier

Hamaya

, et al. Sleeping difficulties, sleep duration, and risk of hypertension in women. Hypertension. 2023;80(11):2407-2414.

Itani

Jike

Watanabe

Kaneita

Short sleep duration and health outcomes: a systematic review, meta-analysis, and meta-regression. Sleep Med. 2017;32:246-256.

Gangwisch

JE.

A review of evidence for the link between sleep duration and hypertension. Am J Hypertens. 2014;27(10):1235-1242.

10.

Candemir

Kızıltunç

Nurkoç

Cihan

Şahinarslan

Predictors of length of hospital stay and in-hospital adverse events in patients with acute decompensated heart failure: in-hospital 24-hour blood pressure monitoring data. Hellenic J Cardiol. 2026;87:42-51.

11.

Tai

BWS

Dawood

Macefield

Yiallourou

. The association between sleep duration and muscle sympathetic nerve activity. Clin Auton Res. 2023;33(6):647-657.

12.

Vaccaro

Kaplan Dor

Nambara

, et al. Sleep loss can cause death through accumulation of reactive oxygen species in the Gut. Cell. 2020;181(6):1307-1328.e1315.

13.

Sang

Lin

Yang

, et al. Prolonged sleep deprivation induces a cytokine-storm-like syndrome in mammals. Cell. 2023;186(25):5500-5516.e5521.

14.

Pinotti

Bertolucci

Frigato

, et al. Chronic sleep deprivation markedly reduces coagulation factor VII expression. Haematologica. 2010;95(8):1429-1432.

15.

Domínguez

Fuster

Fernández-Alvira

, et al. Association of sleep duration and quality with subclinical atherosclerosis. J Am Coll Cardiol. 2019;73(2):134-144.

16.

Tobaldini

Costantino

Solbiati

, et al. Sleep, sleep deprivation, autonomic nervous system and cardiovascular diseases. Neurosci Biobehav Rev. 2017;74(Pt B):321-329.

17.

Cherubini

Cheng

Williams

MacDonald

MJ.

Sleep deprivation and endothelial function: reconciling seminal evidence with recent perspectives. Am J Physiol Heart Circ Physiol. 2021;320(1):H29-H35.

18.

Yamak

Candemir

Kızıltunç

Özdemir

Gülbahar

Şahinarslan

Evaluating SCUBE-1 as predictive biomarker for hypertension-mediated organ damage: a comparative study. Rev Cardiovasc Med. 2025;26(1):25832.

19.

Konukoglu

Uzun

Endothelial dysfunction and hypertension. Adv Exp Med Biol. 2017;956:511-540.

20.

Lüscher

TF.

Imbalance of endothelium-derived relaxing and contracting factors. A new concept in hypertension?

Am J Hypertens. 1990;3(4):317-330.

21.

Ilyas

Little

, et al. Endothelial dysfunction in atherosclerotic cardiovascular diseases and beyond: from mechanism to pharmacotherapies. Pharmacol Rev. 2021;73(3):924-967.

22.

Grgic

Kaistha

Hoyer

Köhler

Endothelial Ca+-activated K+ channels in normal and impaired EDHF-dilator responses—relevance to cardiovascular pathologies and drug discovery. Br J Pharmacol. 2009;157(4):509-526.

23.

Barton

Yanagisawa

Endothelin: 30 years from discovery to therapy. Hypertension. 2019;74(6):1232-1265.

24.

Weil

Mestek

Westby

, et al. Short sleep duration is associated with enhanced endothelin-1 vasoconstrictor tone. Can J Physiol Pharmacol. 2010;88(8):777-781.

25.

Palma

Gabriel

Jr Bignotto

Tufik

Paradoxical sleep deprivation increases plasma endothelin levels. Braz J Med Biol Res. 2002;35(1):75-79.

26.

Yang

, et al. Signaling pathways in vascular function and hypertension: molecular mechanisms and therapeutic interventions. Sig Transduct Target Ther. 2023;8(1):168.

27.

Ling

Mustafa

Murugan

DD.

Therapeutic implications of nitrite in hypertension. J Cardiovasc Pharmacol. 2020;75(2):123-134.

28.

Ahmad

Noordin

Adnan

Safuan

Ab Aziz

CB.

Vascular endothelium dysfunction in REM sleep deprivation: prelude to cardiovascular disease. Int J Cardiol. 2019;297:27.

29.

Kapás

Fang

Krueger

JM.

Inhibition of nitric oxide synthesis inhibits rat sleep. Brain Res. 1994;664(1-2):189-196.

30.

Cespuglio

Amrouni

Meiller

Buguet

Gautier-Sauvigné

Nitric oxide in the regulation of the sleep-wake states. Sleep Med Rev. 2012;16(3):265-279.

31.

Stockelman

Bain

Goulding

, et al. Negative influence of insufficient sleep on endothelial vasodilator and fibrinolytic function in hypertensive adults. Hypertension. 2021;78(6):1829-1840.

32.

Bain

Weil

Diehl

Greiner

Stauffer

DeSouza

CA.

Insufficient sleep is associated with impaired nitric oxide-mediated endothelium-dependent vasodilation. Atherosclerosis. 2017;265:41-46.

33.

Bouras

Deftereos

Tousoulis

, et al. Asymmetric Dimethylarginine (ADMA): a promising biomarker for cardiovascular disease? Curr Top Med Chem. 2013;13(2):180-200.

34.

Sheikh Rezaei

Weisshaar

Litschauer

Gouya

Ohrenberger

Wolzt

. ADMA and NT pro-BNP are associated with overall mortality in elderly. Eur J Clin Invest. 2019;49(1):e13041.

35.

Słomko

Zawadka-Kunikowska

Kozakiewicz

, et al. Hemodynamic, autonomic, and vascular function changes after sleep deprivation for 24, 28, and 32 hours in healthy men. Yonsei Med J. 2018;59(9):1138-1142.

36.

Aribas

Kayrak

Tekinalp

, et al. The relationship between serum asymmetric dimethylarginine levels and subjective sleep quality in normotensive patients with type 2 diabetes mellitus. Korean J Intern Med. 2015;30(3):316-324.

37.

Sakurada

Shichiri

Imamura

Azuma

Hirata

Nitric oxide upregulates dimethylarginine dimethylaminohydrolase-2 via cyclic GMP induction in endothelial cells. Hypertension. 2008;52(5):903-909.

38.

Kopaliani

Jarzebska

Billoff

, et al. Overexpression of dimethylarginine dimethylaminohydrolase 1 protects from angiotensin II-induced cardiac hypertrophy and vascular remodeling. Am J Physiol Heart Circ Physiol. 2021;321(5):H825-H838.

39.

Palm

Onozato

Luo

Wilcox

CS.

Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. Am J Physiol Heart Circ Physiol. 2007;293(6):H3227-H3245.

40.

Xiao

Wang

Liang

Sun

ZL.

Procyanidin B2 from lotus seedpod regulate NO/ADMA/DDAH pathway to treat insomnia in rats. Fundam Clin Pharmacol. 2019;33(5):549-557.

41.

Xiao

Wang

Luo

XY.

SZSJ protects against insomnia by a decrease in ADMA level and an improvement in DDAH production in sleep-deprived rats. Life Sci. 2018;209:97-102.

42.

Jiang

Gan

, et al. REM sleep deprivation induces endothelial dysfunction and hypertension in middle-aged rats: roles of the eNOS/NO/cGMP pathway and supplementation with L-arginine. PLoS One. 2017;12(8):e0182746.

43.

Jia

Aroor

Jia

Sowers

JR.

Endothelial cell senescence in aging-related vascular dysfunction. Biochim Biophys Acta Mol Basis Dis. 2019;1865(7):1802-1809.

44.

Varadharaj

Porter

Pleister

, et al. Endothelial nitric oxide synthase uncoupling: a novel pathway in OSA induced vascular endothelial dysfunction. Respir Physiol Neurobiol. 2015;207:40-47.

45.

Greenlund

Carter

JR.

Sympathetic neural responses to sleep disorders and insufficiencies. Am J Physiol Heart Circ Physiol. 2022;322(3):H337-H349.

46.

Thomas

Calhoun

Sleep, insomnia, and hypertension: current findings and future directions. J Am Soc Hypertension. 2017;11(2):122-129.

47.

Khan

Lip

GYH

Shantsila

Heart rate variability in atrial fibrillation: the balance between sympathetic and parasympathetic nervous system. Eur J Clin Invest. 2019;49(11):e13174.

48.

Schlagintweit

Laharnar

Glos

, et al. Effects of sleep fragmentation and partial sleep restriction on heart rate variability during night. Sci Rep. 2023;13(1):6202.

49.

Wehrens

Hampton

Skene

DJ.

Heart rate variability and endothelial function after sleep deprivation and recovery sleep among male shift and non-shift workers. Scand J Work Environ Health. 2012;38(2):171-181.

50.

Zhong

Hilton

Gates

, et al. Increased sympathetic and decreased parasympathetic cardiovascular modulation in normal humans with acute sleep deprivation. J Appl Physiol. 2005;98(6):2024-2032.

51.

Dettoni

Consolim-Colombo

Drager

, et al. Cardiovascular effects of partial sleep deprivation in healthy volunteers. J Appl Physiol. 2012;113(2):232-236.

52.

Lusardi

Zoppi

Preti

Pesce

Piazza

Fogari

Effects of insufficient sleep on blood pressure in hypertensive patients: a 24-h study. Am J Hypertension. 1999;12(1 Pt 1):63-68.

53.

Liu

Wang

Sun

Wang

Tan

Wang

WZ.

Sleep deprivation reduces the baroreflex sensitivity through elevated angiotensin (Ang) II subtype 1 receptor expression in the nucleus tractus solitarii. Front Neurosci. 2024;18:1401530.

54.

Faraut

Boudjeltia

Vanhamme

Kerkhofs

Immune, inflammatory and cardiovascular consequences of sleep restriction and recovery. Sleep Med Rev. 2012;16(2):137-149.

55.

Sauvet

Drogou

Bougard

, et al. Vascular response to 1 week of sleep restriction in healthy subjects. A metabolic response? Int J Cardiol. 2015;190:246-255.

56.

Sahu

Biswas

Prajapati

Singh

Samant

Khare

Interleukin-17-A multifaceted cytokine in viral infections. J Cell Physiol. 2021;236(12):8000-8019.

57.

Orejudo

García-Redondo

Rodrigues-Diez

, et al. Interleukin-17A induces vascular remodeling of small arteries and blood pressure elevation. Clin Sci. 2020;134(5):513-527.

58.

Van Leeuwen

Lehto

Karisola

, et al. Sleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP. PLoS One. 2009;4(2):e4589.

59.

Bendet

Hamarshi

Lellouche

Avidan

Hanuka

Blum

Sleep deprivation and endothelial function. Isr Med Assoc J. 2025;27(10):659-663.

60.

Sauvet

Leftheriotis

Gomez-Merino

, et al. Effect of acute sleep deprivation on vascular function in healthy subjects. J Appl Physiol. 2010;108(1):68-75.

61.

Meier-Ewert

Ridker

Rifai

, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol. 2004;43(4):678-683.

62.

Nag

Pradhan

RK.

Sleep deprivation and level of C-reactive protein. Biol Rhythm Res. 2011;42(3):209-218.

63.

Choshen-Hillel

Ishqer

Mahameed

, et al. Acute and chronic sleep deprivation in residents: cognition and stress biomarkers. Med Educ. 2021;55(2):174-184.

64.

Ling

Cook

Grimm

Aldokhayyil

Gomez

Brown

The effect of race and shear stress on CRP-induced responses in endothelial cells. Mediat Inflamm. 2021;2021:6687250.

65.

Irwin

Olmstead

Carroll

JE.

Sleep disturbance, sleep duration, and inflammation: a systematic review and meta-analysis of cohort studies and experimental sleep deprivation. Biol Psychiatry. 2016;80(1):40-52.

66.

Bin Heyat

Akhtar

Sultana

, et al. Role of oxidative stress and inflammation in insomnia sleep disorder and cardiovascular diseases: herbal antioxidants and anti-inflammatory coupled with insomnia detection using machine learning. Curr Pharmac Design. 2022;28(45):3618-3636.

67.

Zhang

Zhao

Zhou

Meng

Zhou

Role of inflammation, immunity, and oxidative stress in hypertension: new insights and potential therapeutic targets. Front Immunol. 2022;13:1098725.

68.

Villafuerte

Miguel-Puga

Rodríguez

Machado

Manjarrez

Arias-Carrión

Sleep deprivation and oxidative stress in animal models: a systematic review. Oxid Med Cell Longev. 2015;2015:234952.

69.

Gopalakrishnan

Cirelli

Sleep deprivation and cellular responses to oxidative stress. Sleep. 2004;27(1):27-35.

70.

Wearick-Silva

Nunes

Luft

, et al. Consequences of post-weaning sleep deprivation on behaviour and oxidative stress parameters in rat plasma and brain. Int J Dev Neurosci. 2023;83(2):216-223.

71.

Nawi

Faris

ANA

Wan Ahmad

WAN

Noordin

Lipid peroxidation in the descending thoracic aorta of rats deprived of REM sleep using the inverted flowerpot technique. Exp Physiol. 2020;105(8):1223-1231.

72.

Liu

, et al. Oral nano-antioxidants improve sleep by restoring intestinal barrier integrity and preventing systemic inflammation. Nation Sci Rev. 2023;10(12):nwad309.

73.

Maki

Burke

Calik

, et al. Sleep fragmentation increases blood pressure and is associated with alterations in the gut microbiome and fecal metabolome in rats. Physiol Genom. 2020;52(7):280-292.

74.

Jiao

Dong

Wang

, et al. Profile of gut flora in hypertensive patients with insufficient sleep duration. J Human Hypertension. 2022;36(4):390-404.

75.

Even

Magzal

Shochat

Haimov

Agmon

Tamir

Microbiota metabolite profiles and dietary intake in older individuals with insomnia of short versus normal sleep duration. Biomolecules. 2024;14(4):419.

76.

Zhu

Liu

, et al. Moderation of gut microbiota and bile acid metabolism by chlorogenic acid improves high-fructose-induced salt-sensitive hypertension in mice. Food Func. 2022;13(13):6987-6999.

77.

Kim

Yadav

Ahn

, et al. A prospective study of total sleep duration and incident metabolic syndrome: the ARIRANG study. Sleep Med. 2015;16(12):1511-1515.

78.

Choi

Kim

, et al. Association between short sleep duration and high incidence of metabolic syndrome in midlife women. Tohoku J Exp Med. 2011;225(3):187-193.

79.

Deng

Tam

Zee

BCY

, et al. Short sleep duration increases metabolic impact in healthy adults: a population-based cohort study. Sleep. 2017;40(10).

80.

Jansen

Burgess

Chervin

, et al. Sleep duration and timing are prospectively linked with insulin resistance during late adolescence. Obesity. 2023;31(4):912-922.

81.

Zuraikat

Laferrère

Cheng

, et al. Chronic insufficient sleep in women impairs insulin sensitivity independent of adiposity changes: results of a randomized trial. Diabetes Care. 2024;47(1):117-125.

82.

Lin

, et al. U-shaped relationships between sleep duration and metabolic syndrome and metabolic syndrome components in males: a prospective cohort study. Sleep Med. 2015;16(8):949-954.

83.

Lin

Tsai

Yeh

MC.

The relationship between insomnia with short sleep duration is associated with hypercholesterolemia: a cross-sectional study. J Adv Nurs. 2016;72(2):339-347.

84.

Gangwisch

Malaspina

Babiss

, et al. Short sleep duration as a risk factor for hypercholesterolemia: analyses of the National Longitudinal Study of Adolescent Health. Sleep. 2010;33(7):956-961.

85.

Chua

Shui

Cazenave-Gassiot

Wenk

Gooley

JJ.

Changes in plasma lipids during exposure to total sleep deprivation. Sleep. 2015;38(11):1683-1691.

86.

Kaneita

Uchiyama

Yoshiike

Ohida

Associations of usual sleep duration with serum lipid and lipoprotein levels. Sleep. 2008;31(5):645-652.

87.

Barragán

Zuraikat

Cheng

, et al. Paradoxical effects of prolonged insufficient sleep on lipid profile: a pooled analysis of 2 randomized trials. J Am Heart Assoc. 2023;12(20):e032078.

88.

Abu-Saleh

Yaseen

Kinaneh

Khamaisi

Abassi

Combination of hyperglycaemia and hyperlipidaemia induces endothelial dysfunction: role of the endothelin and nitric oxide systems. J Cell Mol Med. 2021;25(4):1884-1895.

89.

Kong

Niu

Yuan

, et al. Interaction of FOXO1 and SUMOylated PPARγ1 induced by hyperlipidemia and hyperglycemia favors vascular endothelial insulin resistance and dysfunction. Vasc Pharmacol. 2022;147:107125.

90.

Redon

Cífková

The metabolic syndrome in hypertension: diagnostic and therapeutic implications. Curr Hypertension Rep. 2007;9(4):305-313.

91.

Mao

Tokudome

Kishimoto

Ghrelin and blood pressure regulation. Curr Hypertension Rep. 2016;18(2):15.

92.

Bełtowski

Role of leptin in blood pressure regulation and arterial hypertension. J Hypertension. 2006;24(5):789-801.

93.

Taheri

Lin

Austin

Young

Mignot

Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med. 2004;1(3):e62.

94.

Deng

Zhang

Ghrelin improves endothelial function and reduces blood pressure in Ang II-induced hypertensive mice: role of AMPK. Clin Exp Hypertension. 2023;45(1):2208774.

95.

Bełtowski

Leptin and the regulation of endothelial function in physiological and pathological conditions. Clin Exp Pharmacol Physiol. 2012;39(2):168-178.

96.

Mellott

Faulkner

JL.

Mechanisms of leptin-induced endothelial dysfunction. Curr Opin Nephrol Hypertension. 2023;32(2):118-123.

97.

Machleidt

Simon

Krapalis

Hallschmid

Lehnert

Sayk

Experimental hyperleptinemia acutely increases vasoconstrictory sympathetic nerve activity in healthy humans. J Clin Endocrinol Metab. 2013;98(3):E491-E496.

98.

Papatriantafyllou

Efthymiou

Zoumbaneas

Popescu

Vassilopoulou

Sleep deprivation: effects on weight loss and weight loss maintenance. Nutrients. 2022;14(8):1549.

99.

Roberts

Vaziri

Wang

Barnard

RJ.

Enhanced NO inactivation and hypertension induced by a high-fat, refined-carbohydrate diet. Hypertension. 2000;36(3):423-429.

100.

Lobato

Filgueira

Akamine

Tostes

Carvalho

Fortes

ZB.

Mechanisms of endothelial dysfunction in obesity-associated hypertension. Brazil J Med Biol Res. 2012;45(5):392-400.

101.

Costello

Gumz

ML.

Circadian rhythm, clock genes, and hypertension: recent advances in hypertension. Hypertension. 2021;78(5):1185-1196.

102.

Crnko

Du Pré

Sluijter

JPG

Van Laake

LW.

Circadian rhythms and the molecular clock in cardiovascular biology and disease. Nat Rev Cardiol. 2019;16(7):437-447.

103.

Kunieda

Minamino

Miura

, et al. Reduced nitric oxide causes age-associated impairment of circadian rhythmicity. Circ Res. 2008;102(5):607-614.

104.

Touitou

Reinberg

Touitou

Association between light at night, melatonin secretion, sleep deprivation, and the internal clock: health impacts and mechanisms of circadian disruption. Life Sci. 2017;173:94-106.

105.

Niu

Zhang

, et al. Chronic sleep deprivation altered the expression of circadian clock genes and aggravated Alzheimer’s disease neuropathology. Brain Pathol. 2022;32(3):e13028.

106.

Anea

Cheng

Sharma

, et al. Increased superoxide and endothelial NO synthase uncoupling in blood vessels of Bmal1-knockout mice. Circ Res. 2012;111(9):1157-1165.

107.

Anea

Zhang

Stepp

, et al. Vascular disease in mice with a dysfunctional circadian clock. Circulation. 2009;119(11):1510-1517.

108.

Qin

Deng

Overexpression of circadian clock protein cryptochrome (CRY) 1 alleviates sleep deprivation-induced vascular inflammation in a mouse model. Immunol Lett. 2015;163(1):76-83.

109.

Okamura

Doi

Goto

Kojima

. Clock genes and salt-sensitive hypertension: a new type of aldosterone-synthesizing enzyme controlled by the circadian clock and angiotensin II. Hypertension Res. 2016;39(10):681-687.

110.

Viswambharan

Carvas

Antic

, et al. Mutation of the circadian clock gene Per2 alters vascular endothelial function. Circulation. 2007;115(16):2188-2195.

111.

Wang

Wen

Wang

, et al. Increased vascular senescence and impaired endothelial progenitor cell function mediated by mutation of circadian gene Per2. Circulation. 2008;118(21):2166-2173.

112.

Takeda

Maemura

Circadian clock and vascular disease. Hypertension Res. 2010;33(7):645-651.

113.

Rhoads

Balagee

Thomas

SJ.

Circadian regulation of blood pressure: of mice and men. Curr Hypertension Rep. 2020;22(6):40.

114.

Zhang

Sun

Jiang

Yang

Chen

Circadian blood pressure rhythm in cardiovascular and renal health and disease. Biomolecules. 2021;11(6):868.

115.

Higashi

Sasaki

, et al. Daily aerobic exercise improves reactive hyperemia in patients with essential hypertension. Hypertension. 1999;33(1):591-597.

116.

Maeda

Tanabe

Tsuk

, et al. Moderate regular exercise increases basal production of nitric oxide in elderly women. Hypertension Res. 2004;27(12):947-953.

117.

Tsukiyama

Ito

Nagaoka

Eguchi

Ogino

Effects of exercise training on nitric oxide, blood pressure and antioxidant enzymes. J Clin Biochem Nutr. 2017;60(3):180-186.

118.

Dobrosielski

Phan

Miller

Bohlen

Douglas-Burton

Knuth

ND.

Associations between vasodilatory capacity, physical activity and sleep among younger and older adults. Eur J Appl Physiol. 2016;116(3):495-502.

119.

Waclawovsky

Pedralli

Eibel

Schaun

Lehnen

AM.

Effects of different types of exercise training on endothelial function in prehypertensive and hypertensive individuals: a systematic review. Arq Bras Cardiol. 2021;116(5):938-947.

120.

Bommarito

Millar

PJ.

Effects of aerobic exercise on ambulatory blood pressure responses to acute partial sleep deprivation: impact of chronotype and sleep quality. Am J Physiol Heart Circ Physiol. 2024;326(1):H291-H301.

121.

Sauvet

Arnal

Tardo-Dino

, et al. Protective effects of exercise training on endothelial dysfunction induced by total sleep deprivation in healthy subjects. Int J Cardiol. 2017;232:76-85.

122.

Papadakis

Forsse

Peterson

MN.

Acute partial sleep deprivation and high-intensity interval exercise effects on postprandial endothelial function. Eur J Appl Physiol. 2020;120(11):2431-2444.

123.

Saputro

Chou

Lin

Tarumi

Liao

YH.

Exercise-mediated modulation of autonomic nervous system and inflammatory response in sleep-deprived individuals: a narrative reviews of implications for cardiovascular health. Auton Neurosci Basic Clin. 2025;259:103256.

124.

Gitanjali

Dhamodharan

Effect of occupational noise on the nocturnal sleep architecture of healthy subjects. Indian J Physiol Pharmacol. 2004;48(1):65-72.

125.

Münzel

Gori

Babisch

Basner

Cardiovascular effects of environmental noise exposure. Eur Heart J. 2014;35(13):829-836.

126.

Herzog

Schmidt

Hahad

, et al. Acute exposure to nocturnal train noise induces endothelial dysfunction and pro-thromboinflammatory changes of the plasma proteome in healthy subjects. Basic Res Cardio. 2019;114(6):46.

127.

Münzel

Daiber

Steven

, et al. Effects of noise on vascular function, oxidative stress, and inflammation: mechanistic insight from studies in mice. Eur Heart J. 2017;38(37):2838-2849.

128.

Schmidt

Basner

Kröger

, et al. Effect of nighttime aircraft noise exposure on endothelial function and stress hormone release in healthy adults. Eur Heart J. 2013;34(45):3508-3514a.

129.

Grassi

Socci

Tempesta

, et al. Flavanol-rich chocolate acutely improves arterial function and working memory performance counteracting the effects of sleep deprivation in healthy individuals. J Hypertension. 2016;34(7):1298-1308.

130.

Baker

Kimpinski

Role of melatonin in blood pressure regulation: an adjunct anti-hypertensive agent. Clin Exp Pharmacol Physiol. 2018;45(8):755-766.

131.

Zou

Yang

, et al. Association between nocturnal light exposure and melatonin in humans: a meta-analysis. Environ Sci Pollut Res Int. 2024;31(3):3425-3434.

132.

Figueiro

Sahin

Wood

Plitnick

Light at night and measures of alertness and performance: implications for shift workers. Biol Res Nurs. 2016;18(1):90-100.

133.

Daugaard

Garde

Bonde

JPE

, et al. Night work, light exposure and melatonin on work days and days off. Chronobiol Int. 2017;34(7):942-955.

134.

Obayashi

Saeki

Iwamoto

Ikada

Kurumatani

Association between light exposure at night and nighttime blood pressure in the elderly independent of nocturnal urinary melatonin excretion. Chronobiol Int. 2014;31(6):779-786.

135.

Sasseville

Paquet

Sévigny

Hébert

Blue blocker glasses impede the capacity of bright light to suppress melatonin production. J Pineal Res. 2006;41(1):73-78.

136.

Lee

Poon

Lee

Chung

Wong

SY.

Controlled-release oral melatonin supplementation for hypertension and nocturnal hypertension: a systematic review and meta-analysis. J Clin Hypertension. 2022;24(5):529-535.

137.

Zhu

Qin

Association between weekend catch-up sleep and cardiovascular disease: evidence from the National Health and Nutrition Examination Surveys 2017-2018. Sleep Health. 2024;10(1):98-103.

138.

Hwangbo

Kim

Chu

Yun

Yang

KI.

Association between weekend catch-up sleep duration and hypertension in Korean adults. Sleep Med. 2013;14(6):549-554.

139.

Haack

Serrador

Cohen

Simpson

Meier-Ewert

Mullington

JM.

Increasing sleep duration to lower beat-to-beat blood pressure: a pilot study. J Sleep Res. 2013;22(3):295-304.

140.

Vierra

Boonla

Prasertsri

Effects of sleep deprivation and 4-7-8 breathing control on heart rate variability, blood pressure, blood glucose, and endothelial function in healthy young adults. Physiol Rep. 2022;10(13):e15389.

141.

Trauer

Qian

Doyle

Rajaratnam

Cunnington

Cognitive behavioral therapy for chronic insomnia: a systematic review and meta-analysis. Ann Intern Med. 2015;163(3):191-204.

142.

Sherwood

Ulmer

, et al. Cognitive behavior therapy for insomnia for untreated hypertension with comorbid insomnia disorder: the SLEEPRIGHT clinical trial. J Clin Hypertension. 2024;26(4):441-447.

143.

Buys

Song

Sun

The efficacy of cognitive behavioral therapy-based interventions on patients with hypertension: a systematic review and meta-analysis. Prevent Med Rep. 2021;23:101477.

144.

McEwen

BS.

Sleep deprivation as a neurobiologic and physiologic stressor: allostasis and allostatic load. Metabolism. 2006;55(10 Suppl 2):S20-S23.

145.

Shu

The effect of cognitive behavioral therapy on the release of interpersonal stress. Work. 2021;69(2):625-636.

146.

Kagota

Morikawa

Ishida

, et al. Vasorelaxant effects of benzodiazepines, non-benzodiazepine sedative-hypnotics, and tandospirone on isolated rat arteries. Eur J Pharmacol. 2021;892:173744.

147.

Hung

Lam

Lau

Yip

Lee

EK.

Effects of hypnotics on nocturnal blood pressure: a systematic review and meta-analysis of randomised controlled trials. Blood Pressure. 2025;34(1):2591457.

148.

Yang

Ren

Cai

, et al. Z-drugs are associated with cardiovascular outcomes among patients with heart failure: a population-based cohort study in Hong Kong. Eur J Prevent Cardiol. Published online March 26, 2025. doi: 10.1093/eurjpc/zwaf128

149.

Xie

Zhu

, et al. Hypnotic use and the risk of cardiovascular diseases in insomnia patients. Eur J Prevent Cardiol. 2025;32(6):466-474.

150.

Sateia

Buysse

Krystal

Neubauer

Heald

JL.

Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017;13(2):307-349.

151.

Smolensky

Hermida

Castriotta

Geng

YJ.

Findings and methodological shortcomings of investigations concerning the relationship between sleep duration and blood pressure: a comprehensive narrative review. J Cardiovasc Develop Dis. 2025;12(3):95.