Circadian Rhythms and Blood Vessel Health: All You Need to Know

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I’ve written extensively on the relationship between sleep and cardiovascular health, and specifically how insufficient sleep leads to reduced endothelial function — an area of research I am extremely interested in.

There are several mechanisms that might be responsible for the negative effects of poor sleep on cardiovascular (CV) health and function, but one in particular has to do with our internal biological rhythms: a.k.a. circadian rhythms. This post is a brief primer on the circadian characteristics of blood vessel function and how insufficient or atypical sleep may disrupt circadian rhythms and promote blood vessel (endothelial) dysfunction and the development of cardiovascular disease.

Along with many other peripheral tissues, endothelial and vascular smooth muscle cells possess their own internal circadian oscillations, and there is increasing evidence that many cardiovascular activities, including endothelial function, exhibit a diurnal pattern.(1, 2) The presence of circadian clocks in vascular cells and time-of-day variance in vascular tone and endothelial function likely anticipate external and internal stimuli. Endothelial function (FMD) has been shown to exhibit a morning nadir and an afternoon peak.(3) — meaning blood vessel function seems to be lowest in the morning and highest in the mid to late afternoon.

This pattern may have relevance to the pathophysiology of CV events such as stroke and heart attacks— as the incidence of acute CV events is higher in the morning, coinciding with the a.m. blood pressure surge, reduced vasodilatory capacity, and increased blood platelet coagulation.(4)

Sleep-deprivation induced endothelial dysfunction could potentially explain and/or exacerbate the incidence of early morning CV events, though this mechanism has not been investigated. There is now emerging evidence that endothelial nitric-oxide synthase (eNOS) signaling (and therefore NO bioavailability) may be under circadian control.(5) The specific time-of-day release of circulating molecules including NO and endothelin 1(ET-1)(6) likely promote optimal endothelial function at various times of day.

The disruption of circadian rhythmicity in vascular function and vascular-function related molecules is likely another mechanism by which acute and chronic sleep deprivation and shift work negatively affect endothelial function.

Experimental data on the effects of sleep deprivation on circadian clock gene expression, circadian rhythmicity, or chronobiological function in humans are limited. Acute overnight sleep deprivation has been shown to alter epigenetic and transcriptional circadian clock gene profiles in humans.(7) Sleep deprivation may promote endothelial dysfunction by altering circadian release profiles of NO, ET-1, and endothelial and vascular smooth muscle cell sensitivity to these vasoactive stimuli. Indeed, animal models of circadian disruption show evidence of vascular senescence, endothelial dysfunction, and loss of diurnal variation in endothelial function and blood pressure.(8)

During sleep, blood pressure and vascular shear stress are reduced. Cellular turnover is also highly active during sleep and thus, reduced vascular stress likely suppresses pro-hypertrophic stimuli and favors repair mechanisms that promote cardiovascular health and reduce disease burden (reviewed in Rana et al).(9)

An absence of the nocturnal blood pressure dip and other regenerative functions at night could impair vascular remodeling, increase vascular and endothelial inflammation and oxidative stress, and promote cell senescence; mechanisms that have been implicated in the pathogenesis of vascular aging.(10) Our cardiovascular system, like all organ systems, needs a rest at night. Depriving it of this recovery time will have detrimental effects in the long-term.

Furthermore, sleep deprivation and shift work require being awake when, according to human biology, one should be sleeping. This likely results in circadian rhythm misalignment. Being awake during the night also exposes individuals to time cues known as zeitgebers (e.g., light, food, and physical activity) that disrupt normal circadian rhythms.(11–13)

As evidence for this, shift workers who suffer from chronic insufficient sleep and an abnormal sleep/wake schedule have disrupted circadian clocks. Furthermore, these individuals do not seem to adapt to this schedule as evidenced by a lack of complete entrainment of their circadian rhythms to the night shift.(14) Thus, both acute sleep deprivation and chronic insufficient or atypical sleep likely cause endothelial dysfunction in part, through adverse effects on circadian rhythms.

Given these data, it seems imperative that we prioritize not only getting ENOUGH sleep, but enough high-quality sleep as well. This means having good sleep “hygiene” (reducing pre-bed lights, noises, etc.) and getting to bed at the “proper” time each night. Moreover, having a consistent sleep schedule (i.e. going to bed and waking up at the same time every day) seems to also be important for promoting optimal cardiovascular health.

There aren’t necessarily suggestions as to how long you should sleep (but probably somewhere between 7–9 hours/night) or when you should go to bed and wake up. This likely depends on your individual preferences and makeup. A genetic basis for sleep patterns definitely exists, so do what makes you feel and perform best, as this is likely what aligns with your unique circadian biology.

References

1. Thosar S, Berman A, Herzig M, et al. Circadian Rhythm of Vascular Function in Midlife Adults. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39(6):1203–11.

2. Thosar SS, Butler MP, Shea SA. Role of the circadian system in cardiovascular disease. The Journal of clinical investigation. 2018;128(6):2157–67.

3. Thosar SS, Berman AM, Herzig MX, Roberts SA, Lasarev MR, Shea SA. Morning impairment in vascular function is unrelated to overnight sleep or the inactivity that accompanies sleep. American Journal of Physiology-Regulatory Integrative and Comparative Physiology. 2018;315(5):R986–93.

4. Crnko S, Du Pré BC, Sluijter JPG, Van Laake LW. Circadian rhythms and the molecular clock in cardiovascular biology and disease. Nature Reviews Cardiology. 2019;16(7):437–47.

5. Paschos G, FitzGerald G. Circadian Clocks and Vascular Function. Circulation research. 2010;106(5):833–41.

6. Elherik K, Khan F, McLaren M, Kennedy G, Belch JJ. Circadian variation in vascular tone and endothelial cell function in normal males. Clin Sci (Lond). 2002;102(5):547–52.

7. Cedernaes J, Osler ME, Voisin S, et al. Acute Sleep Loss Induces Tissue-Specific Epigenetic and Transcriptional Alterations to Circadian Clock Genes in Men. The Journal of Clinical Endocrinology & Metabolism. 2015;100(9):E1255–61.

8. Shang X, Pati P, Anea CB, Fulton DJR, Rudic RD. Differential Regulation of BMAL1, CLOCK, and Endothelial Signaling in the Aortic Arch and Ligated Common Carotid Artery. Journal of vascular research. 2016;53(5–6):269–78.

9. Rana S, Prabhu SD, Young ME. Chronobiological Influence Over Cardiovascular Function. Circulation research. 2020;126(2):258–79.

10. Ungvari Z, Tarantini S, Sorond F, Merkely B, Csiszar A. Mechanisms of Vascular Aging, A Geroscience Perspective: JACC Focus Seminar. Journal of the American College of Cardiology. 2020;75(8):931–41.

11. Wehrens SMT, Christou S, Isherwood C, et al. Meal Timing Regulates the Human Circadian System. Current Biology. 2017;27(12):1768–1775.e3.

12. Fonken LK, Aubrecht TG, Meléndez-Fernández OH, Weil ZM, Nelson RJ. Dim Light at Night Disrupts Molecular Circadian Rhythms and Increases Body Weight. Journal of Biological Rhythms. 2013;28(4):262–71.

13. Wolff CA, Esser KA. Exercise Timing and Circadian Rhythms. Curr Opin Physiol. 2019;10:64–9.

14. Boivin DB, Tremblay GM, James FO. Working on atypical schedules. Sleep medicine. 2007;8(6):578–89.

PhD candidate at the University of Florida — Science writing with a particular focus on exercise and nutrition interventions, aging, health, and disease.

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