Regular aerobic exercise counteracts endothelial vasomotor dysfunction associated with insufficient sleep

Abstract

Insufficient sleep is associated with endothelial vasomotor dysfunction and increased cardiovascular risk. Regular aerobic exercise is an effective lifestyle strategy for improving endothelial function and, in turn, reducing cardiovascular risk. We tested the hypotheses that regular aerobic exercise would 1) improve endothelial vasodilation and 2) decrease endothelin (ET)-1-mediated vasoconstrictor tone in middle-aged adults who chronically sleep <7 h/night. Thirty-six healthy, middle-aged adults were studied: 16 with normal sleep duration (age: 57 ± 2 yr; sleep duration: 7.4 ± 0.1 h/night) and 20 with short sleep duration (age: 56 ± 1 yr; sleep duration: 6.2 ± 0.1 h/night). The 20 short sleepers completed a 3-mo aerobic exercise training intervention. Forearm blood flow was determined (via plethysmography) in response to intra-arterial acetylcholine (ACh), BQ-123 (ET_A receptor antagonist), ACh + BQ-123, and sodium nitroprusside. Forearm blood flow responses to ACh were lower (∼20%; P < 0.05) in the short (from 4.2 ± 0.2 to 10.5 ± 0.6 mL/100 mL tissue/min) versus normal (4.2 ± 0.2 to 12.7 ± 0.6 mL/100 mL tissue/min) sleepers. In response to BQ-123, the short-sleep group had a significantly greater increase in resting forearm blood flow than the normal-sleep group (∼25% vs. ∼8%). ACh + BQ-123 resulted in a significant (∼25%) increase in the ACh-mediated vasodilation in the short-sleep group only. After exercise training, although nightly sleep duration was unchanged (6.4 ± 0.1 h/night), ACh-mediated vasodilation was significantly higher (∼20%), ET-1-mediated vasoconstriction was significantly lower (∼80%), and the vasodilator response to ACh was not increased with ET_A receptor blockade. Regular aerobic exercise, independent of changes in nightly sleep duration, can counteract insufficient sleep-related endothelial vasomotor dysfunction.

NEW & NOTEWORTHY Habitual insufficient nightly sleep (<7 h/night) is associated with increased risk of cardiovascular disease and events. Endothelial dysfunction, specifically reduced endothelium-dependent vasodilation and increased endothelin (ET)-1-mediated vasoconstriction, is considered to be a major contributing mechanism underlying increased vascular risk with insufficient sleep. In contrast to insufficient sleep, regular aerobic exercise enhances endothelial vasomotor function, reducing the risk of cardiovascular disease and associated events. In the present study, we determined the effects of aerobic exercise training on endothelium-dependent vasodilation and ET-1 vasoconstriction in adults who habitually sleep <7 h/night. After exercise training, although nightly sleep duration was unchanged, endothelium-dependent vasodilation was significantly enhanced and ET-1-mediated vasoconstrictor tone was significantly reduced in adults who sleep <7 h/night. Regular aerobic exercise training can mitigate insufficient sleep-related endothelial vasomotor dysfunction and, in turn, potentially reduce the cardiovascular risk associated with habitual insufficient nightly sleep.

INTRODUCTION

Insufficient nightly sleep, defined as sleeping less than 7 h/night (1), is now recognized as an independent risk factor for cardiovascular disease (CVD) morbidity and mortality (2–5). Endothelial dysfunction, specifically impaired endothelial vasomotor function, is considered to be a major contributing mechanism underlying increased vascular risk with insufficient sleep (6–9). Indeed, nitric oxide-mediated endothelium-dependent vasodilation has been shown to be significantly lower in adults who habitually sleep <7 h/night compared with adults who sleep ≥7 h/night (6). In addition, insufficient sleep is associated with increased endothelin (ET)-1 vasoconstrictor tone (9). Reduced nitric oxide-mediated vasodilation and increased ET-1 vasoconstrictor tone are hallmark characteristics of endothelial dysfunction and central precipitating events in the development of CVD (10–12).

In contrast to insufficient sleep, regular aerobic exercise is associated with enhanced endothelial vasomotor function and lower CVD risk and burden (13–18). For example, we (13, 14, 18) and others (15–18) have demonstrated that habitual aerobic exercise improves endothelium-dependent vasodilation and reduces ET-1-mediated vasoconstrictor tone in middle-aged and older adults regardless of underlying risk factors such as obesity, metabolic syndrome, and hypertension. In addition, regular aerobic exercise can often mitigate the CVD risk-associated poor health behaviors such as cigarette smoking (19) or pathological conditions such as obesity (14, 20) and type 2 diabetes (21). Currently, it is unknown whether regular aerobic exercise can counteract the negative impact of insufficient sleep on endothelial vasomotor regulation.

Accordingly, we tested the hypotheses that regular aerobic exercise would 1) improve endothelium-dependent vasodilation and 2) decrease ET-1-mediated vasoconstrictor tone in middle-aged adults who chronically sleep <7 h/night. To comprehensively address these hypotheses, we used both a cross-sectional study design and an intervention model to confirm the negative influence of insufficient sleep on endothelial vasomotor function and to determine the effects of aerobic exercise training on endothelium-dependent vasodilation and ET-1 vasoconstriction in adults who habitually sleep <7 h/night.

METHODS

Subjects

Thirty-six healthy, middle-aged adults (age range: 44–64 yr) were studied: 16 with normal sleep duration (10 M/6 F; range: 7.0–8.3 h/night) and 20 with chronic short sleep duration (11 M/9 F; 5.0–6.9 h/night). All subjects were normotensive and free of overt cardiovascular disease as assessed by medical history, physical examination, fasting blood chemistries, and ECG measured at rest and during incremental exercise performed to exhaustion. Subjects were nonsmokers, were not taking medications (including vitamins or other dietary supplements), and had not performed regular aerobic exercise for at least 1 year before the start of the study. All women were at least 1 year postmenopausal and had never taken or had discontinued use of hormone replacement therapy at least 1 year before the start of the study. Prior to participation, written informed consent was obtained from each subject. All procedures were performed as per institutional guidelines approved by the Institutional Review Board of the University of Colorado Boulder.

Sleep Duration

Sleep duration was assessed using a component of the Stanford Physical Activity Questionnaire (6, 8, 9, 22). Subjects were asked the average number of hours/night they slept over the past 7 days and were asked about their sleep duration on weeknights (i.e., Sunday–Thursday) and weekend nights (i.e., Friday–Saturday) separately. Nightly average reported sleep duration was calculated as the weighted average of week and weekend night values: [(5 × weekday sleep duration) + (2 × weekend sleep duration)/7] (23–25). Subjects were divided into two groups based on their reported sleep duration: 7 to 9 h/night = “normal sleep duration” and <7 h/night = “short sleep duration.” These criteria were chosen based on previous reports indicating that habitual sleep duration of <7 h/night is associated with increased cardiometabolic risk and diseases such as hypertension, diabetes, coronary artery disease, and stroke (2–4, 26–28).

Body Composition

Body mass was measured to the nearest 0.1 kg using a medical beam balance (Detecto, Webb City, MO). Body mass index was calculated as the weight in kilograms divided by the height in meters squared. The percentage of body fat was determined by dual-energy X-ray absorptiometry (Lunar Corp., Madison, WI).

Maximal Oxygen Consumption

Aerobic fitness was assessed by incremental treadmill exercise using a modified Balke protocol. Maximal oxygen consumption (V̇O_2max) was measured with online computer-assisted open-circuit spirometry, as previously described (29). Heart rate was measured by electrocardiography throughout the exercise test, and the rating of perceived exertion and total exercise time to exhaustion were recorded.

Metabolic Measurements

Fasting plasma lipid and lipoprotein, glucose, and insulin concentrations were determined using standard techniques by the clinical laboratory affiliated with the Clinical and Translational Research Center at the University of Colorado Boulder.

Intra-arterial Infusion Protocol

All measurements were performed between 7:00 AM and 10:00 AM after a 10-h overnight fast in a temperature-controlled room as previously described by our laboratory (14). Briefly, a 5-cm, 20-gauge catheter was inserted into the brachial artery of the nondominant arm under local anesthesia (1% lidocaine). Forearm blood flow (FBF) was measured using strain gauge venous occlusion plethysmography at rest and in response to each pharmacological agent. After the measurement of resting blood flow for 5 min, acetylcholine (IOLAB Pharmaceuticals, Duluth, GA) was infused intraarterially at rates of 4.0, 8.0, and 16.0 μg/100 mL tissue/min, and sodium nitroprusside (Nitropress; Abbott Laboratories, Abbott Park, IL) at 1.0, 2.0, and 4.0 μg/100 mL tissue/min for 5 min at each dose. Flow was recorded four times each minute at rest and throughout each drug infusion protocol. Flows during the last minute of rest and each drug dose were measured and the mean value reported. After the initial infusions of acetylcholine and sodium nitroprusside, BQ-123 (Clinalfa AG, Bubendorf, Switzerland; IND: 58,501), a selective ET_A receptor antagonist, was infused at a rate of 100 nmol/min for 60 min, and FBF was measured every 10 min for at least 1 min and the mean value reported. After 60 min, infusion of BQ-123 was continued at the same dose, and FBF was measured during co-administration of acetylcholine as performed earlier. Heart rate and mean arterial pressure (MAP, calculated as 1/3 pulse pressure plus diastolic pressure) were measured continuously throughout the infusion protocol. Consistent with the low doses of each vasoactive agent used, the infusion protocols produced no changes in heart rate or MAP. Forearm volume was determined by the water displacement method.

Exercise Intervention

The subjects with short sleep duration participated in a 3-mo home-based aerobic exercise-training program that has been previously described by our laboratory (13, 14, 18). Subjects participated in a supervised orientation, after which they exercised on their own. For the first 2–3 wk of the exercise program, subjects walked for 30 min per day, 3–4 days per week, at an intensity of ∼60% of their individually determined maximal heart rate. As their tolerance for exercise improved, subjects were asked to increase the duration of exercise to 40–45 min per day and the intensity of their exercise to 70%–75% of their maximal heart rate for 5–6 days per week. Compliance was documented with the use of heart rate monitors (Polar Electro, Kempele, Finland) and personal activity logs. The subjects were asked to record their prescribed exercise activity as well as any other additional physical activity on a daily basis. Both the heart rate monitors and physical activity logs were returned to the laboratory every 2 wk and analyzed.

Statistical Analysis

Differences in subject baseline physical and metabolic characteristics between the normal-sleep and short-sleep groups were determined by one-way ANOVA. Group differences in the FBF responses to acetylcholine, sodium nitroprusside, BQ-123, and acetylcholine + BQ-123 were determined by repeated-measures ANOVA. When indicated by a significant F value, a Newman–Keuls post hoc test was performed to identify differences among the groups. Changes in physical and metabolic characteristics as well as FBF responses to acetylcholine, sodium nitroprusside, BQ-123, and acetylcholine + BQ-123 resulting from the exercise intervention in the short sleep duration group were assessed by repeated-measures ANOVA. There were no significant sex interactions; thus, all data were pooled and presented together. All data are expressed as means ± SE. Statistical significance was set a priori at P < 0.05.

RESULTS

Selected subject characteristics are presented in Table 1. There were no significant group differences in age, anthropometric, hemodynamic, or metabolic variables, and all values were within clinically normal ranges. However, the short sleep duration group slept ∼71.3 min/night less (P < 0.05) than the normal sleep duration group.

Table 1.

Selected subject characteristics

		Short Sleep
Variable	Normal sleep	Before exercise	After exercise
Men/women	10/6	11/9
Age, yr	57 ± 2	56 ± 1
Nightly sleep duration, h	7.4 ± 0.1	6.2 ± 0.1*	6.4 ± 0.1
Body mass, kg	82.9 ± 3.9	89.5 ± 2.1	89.0 ± 2.0
BMI, kg/m2	28.2 ± 0.9	29.8 ± 0.5	29.6 ± 0.5
Percentage body fat	34.1 ± 2.6	35.9 ± 1.9	35.4 ± 1.9
Systolic BP, mmHg	117 ± 2	119 ± 2	118 ± 2
Diastolic BP, mmHg	72 ± 1	75 ± 2	74 ± 2
Total cholesterol, mg/dL	201.3 ± 6.7	208.9 ± 7.1	189.4 ± 8.0
HDL-cholesterol, mg/dL	56.3 ± 3.6	52.5 ± 3.9	48.6 ± 3.9
LDL-cholesterol, mg/dL	123.1 ± 5.4	130.0 ± 6.5	116.0 ± 6.8
Triglycerides, mg/dL	111.6 ± 11.7	133.5 ± 12.3	125.3 ± 15.0
Glucose, mg/dL	90.3 ± 1.7	87.3 ± 2.5	88.5 ± 2.0
Insulin, µU/mL	9.2 ± 0.8	8.7 ± 0.5	7.3 ± 0.7

Values are means ± SE. BMI, body mass index; BP, blood pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein. Data were analyzed using one-way ANOVA.

*P < 0.05 vs. normal sleep.

Cross-Sectional Study: FBF Responses to Vasodilator and Vasoconstrictor Agents in the Normal and Short Sleep Duration Groups

Group differences in FBF responses to acetylcholine and sodium nitroprusside are shown in Fig. 1. The FBF responses to acetylcholine were significantly lower (∼20%) in the short-sleep (from 4.2 ± 0.2 to 10.5 ± 0.6 mL/100 mL tissue/min) compared with the normal-sleep (from 4.2 ± 0.2 to 12.7 ± 0.6 mL/100 mL tissue/min) group. Correspondingly, total FBF to acetylcholine (area under the blood flow curve) was ∼25% lower (P < 0.05) in the short sleep duration group. FBF responses to sodium nitroprusside were not significantly different between the groups. The FBF response to the selective ET_A receptor antagonist, BQ-123, was significantly different between the groups (Fig. 2). In normal-sleep adults, resting FBF was not significantly altered by BQ-123, whereas in the short-sleep group, BQ-123 elicited a significant vasodilator response (∼25%). Co-infusion of acetylcholine and BQ-123 resulted in a significant increase (∼25%) in the vasodilator response to acetylcholine in the short-sleep group but not the normal-sleep group (Fig. 3).

Figure 1.

Forearm blood flow responses (A), total forearm blood flow (area under the curve) to acetylcholine (B), and sodium nitroprusside (C) in the normal (n = 16) and short (n = 20) sleep duration groups; n = number of subjects. Data were analyzed using repeated-measures ANOVA followed by Newman-Keuls post hoc analysis (A and C) and one-way ANOVA (B). Values are means ± SE. *P < 0.05 vs. normal sleep duration group.

Figure 2.

Forearm blood flow responses to BQ-123 (selective ET_A blockade) in normal (n = 16) and short (n = 20) sleep duration groups; n = number of subjects. Data were analyzed using repreated-measures ANOVA. Values are means ±SE. The P value refers to the difference in the forearm blood flow (FBF) responses to BQ-123 between the groups.

Figure 3.

Forearm blood flow responses and total forearm blood flow to acetylcholine in the absence and presence of BQ-123 (ET_A receptor antagonist) in normal (n = 16) and short (n = 20) sleep duration groups; n = number of subjects. Data were analyzed using repeated-measures ANOVA followed by Newman-Keuls post hoc analysis (top) and one-way ANOVA (bottom). Values are means ± SE. *P < 0.05 vs. saline.

Intervention Study: Effects of Aerobic Exercise Intervention on FBF Responses to Vasodilator and Vasoconstrictor Agents in the Short-Sleep Group

All 20 adults in the short sleep duration group completed the 3-mo home-based exercise intervention. They exercised for an average of 4.7 ± 0.2 days each week for 52.3 ± 1.7 min/day at an intensity of 72% ± 1% of maximal heart rate. There were no significant changes in anthropometric, hemodynamic, or metabolic variables in response to exercise training. In addition, reported nightly sleep duration was also not significantly different after compared with before the exercise intervention (Table 1). Although V̇O_2max was unchanged, aerobic exercise training significantly increased exercise time to exhaustion by ∼20% and significantly decreased both heart rate and rating of perceived exertion (Borg scale) at the same absolute submaximal level of exercise (70% of baseline V̇O_2max) (Table 2). Figure 4 shows the FBF responses to acetylcholine and sodium nitroprusside before and after the exercise intervention. Aerobic exercise training significantly increased FBF responses to acetylcholine (from 4.1 ± 0.2 to 13.1 ± 0.6 mL/100 mL tissue/min vs. 4.2 ± 0.2 to 10.5 ± 0.6 mL/100 mL tissue/min). Correspondingly, total FBF to acetylcholine was ∼30% higher (62.9 ± 4.3 vs. 46.8 ± 3.2 mL/100 mL tissue; P < 0.05) after the exercise intervention. FBF responses to sodium nitroprusside did not change significantly in response to the aerobic exercise intervention. After the exercise intervention, BQ-123 elicited a small, nonsignificant increase in resting FBF in the previously sedentary short sleepers compared with significant vasodilatation (∼25%) before the exercise training program (Fig. 5). Before aerobic exercise training, the co-infusion of BQ-123 with acetylcholine resulted in an enhanced (∼25%; P < 0.05) vasodilator response to acetylcholine; however, after the exercise intervention, the addition of BQ-123 did not significantly affect the vasodilator response to acetylcholine (Fig. 6). FBF responses to acetylcholine in the presence (from 3.8 ± 0.2 to 13.3 ± 0.0 mL/100 mL tissue/min) and absence (from 4.1 ± 0.2 to 13.1 ± 0.6 mL/100 mL tissue/min) of BQ-123 were almost identical. Indeed, the total blood flow response to acetylcholine with (69.4 ± 4.2 mL/100 mL tissue) or without BQ-123 (62.9 ± 4.3 mL/100 mL tissue) was similar after exercise training.

Table 2.

Responses to exercise training

Variable	Before exercise	After exercise
V̇O2max, mL/kg/min	29.9 ± 1.5	30.6 ± 1.3
Treadmill exercise time, min	9.9 ± 0.3	11.0 ± 0.3*
Submaximal HR, beats/min	139 ± 3	129 ± 3*
Submaximal RPE	14.0 ± 0.4	12.0 ± 0.5*

Values are means ± SE; n = 20. HR, heart rate; RPE, rating of perceived exertion; V̇O_2max, maximal oxygen consumption. Data were analyzed using repeated-measure ANOVA.

*P < 0.05 vs. before exercise.

Figure 4.

Forearm blood flow responses (A), total forearm blood flow (area under the curve) to acetylcholine (B) and sodium nitroprusside (C) before and after 3 mo of aerobic exercise training in adults with short sleep duration (n = 20); n = number of subjects. Data were analyzed using repeated-measure ANOVA followed by Newman-Keuls post hoc analysis (A and C) and one-way ANOVA (B). Values are means ± SE. *P < 0.05 vs. before exercise training.

Figure 5.

Forearm blood flow (FBF) responses to the selective ET_A receptor antagonist BQ-123 before and after 3 mo of aerobic exercise training in adults with short sleep duration (n = 20); n = number of subjects. The P value refers to the difference in the FBF response (main effect) to BQ-123 before vs. after the exercise training. Data were analyzed using repeated-measure ANOVA. Values are means ± SE. *P < 0.05 vs. before exercise training.

Figure 6.

Forearm blood flow responses and total forearm blood flow to acetylcholine in the absence and presence of BQ-123 (ET_A receptor antagonist) before and after 3 mo of aerobic exercise training in adults with short sleep duration (n = 20); n = number of subjects. Data were analyzed using repeated-measure ANOVA followed by Newman-Keuls post hoc analysis (top) and one-way ANOVA (bottom). Values are means ± SE. *P < 0.05 vs. saline.

DISCUSSION

The primary new finding of the present study is that regular aerobic exercise improves endothelial vasomotor function in adults who habitually sleep <7 h/night. Indeed, aerobic exercise training enhanced endothelium-dependent vasodilation and reduced ET-1-mediated vasoconstrictor tone in adults with insufficient sleep. Furthermore, the exercise-induced improvement in endothelial vasodilation is due, primarily, to lowered ET-1 vasoconstriction. This is the first study, to our knowledge, to determine whether moderate-intensity aerobic exercise training can mitigate insufficient sleep-related endothelial dysfunction.

The vascular endothelium regulates vascular tone and, thus, in turn, vascular health and function (30). Endothelial dysfunction, specifically imbalance in endothelial vasodilation and vasoconstriction, is a principal characteristic in a series of phenotypic changes in endothelial cells that lead to the development and progression of CVD (31). Several studies have demonstrated that impaired endothelium-dependent vasodilation is associated with increased CVD risk, disease severity, and outcome (11, 32–34). For example, a meta-analysis of 23 studies indicated that endothelium-dependent vasodilation was significantly and robustly inversely related with both CVD development and future CVD-related events (32). Moreover, endothelial dysfunction is a common, hallmark feature of essentially all CVD risk factors and is omnipresent in cardiometabolic, cerebrovascular, and immune disease states (33, 35–37). It is not surprising then that we (6) and others (38, 39) have demonstrated that chronic and acute insufficiency in nightly sleep is associated with decreased endothelium-dependent vasodilation. For example, Bain et al. (6) demonstrated that nitric oxide-mediated endothelium-dependent vasodilation is markedly reduced in adults who chronically sleep <7 h/night compared with adults with normal sleep duration. The results of the present study confirm and significantly extend these findings. Consistent with these prior findings, we show that the FBF responses to the endothelial agonist acetylcholine are blunted (∼20%) in a similar fashion in a group of otherwise healthy short sleepers. Importantly, however, we demonstrate for the first time that regular aerobic exercise reverses this sleep-related impairment in endothelial vasodilator function. Three months of regular, moderate aerobic exercise, primarily walking, increased the FBF response to acetylcholine by ∼25% (P < 0.05) in the short-sleep adults compared with before the exercise intervention. In fact, after the exercise intervention, endothelium-dependent vasodilation in the short sleep duration group was comparable with that of the normal sleepers even though nightly sleep duration was unchanged.

In addition to improving endothelial vasodilation, the 3-mo, home-based moderate aerobic exercise intervention also reduced ET-1-mediated vasoconstriction in adults who habitually sleep <7 h/night. ET-1 is a potent vasoconstrictor peptide produced and released by the endothelium, and elevated ET-1 system activity and vasoconstrictor tone are associated with increased CVD risk, development, and severity (36, 40–42). We have previously shown that ET_A receptor-mediated ET-1 vasoconstrictor tone is enhanced with insufficient sleep (9). Consistent with our previous study, the short sleep duration group in the present study demonstrated significantly higher vasodilator response to the ET_A receptor-antagonist BQ-123 compared with the normal sleepers, indicative of greater ET-1 vasoconstrictor tone with insufficient sleep. After the exercise intervention, however, the vascular response to ET_A blockade was markedly diminished in the short-sleep adults and comparable with that of the normal-sleep adults, suggesting that regular aerobic exercise alleviated the ET-1 vasoconstrictor burden associated with insufficient sleep.

A seminal finding of the present study is that the impairment in acetylcholine-stimulated endothelium-dependent vasodilatation with insufficient sleep is directly linked to increased ET_A receptor-mediated ET-1 vasoconstriction. Indeed, in stark contrast to the normal sleepers, the co-infusion of BQ-123 significantly increased (∼25%) the vasodilator response to acetylcholine (compared with acetylcholine alone) in the short sleepers, demonstrating that diminished endothelium-dependent vasodilatation with insufficient sleep is due, in large part, to enhanced ET-1-mediated vasoconstrictor tone. The influence of augmented ET-1 vasoconstriction on sleep-related endothelial vasodilator dysfunction is further illustrated by the integrated beneficial effects of exercise training on vasomotor function in the short sleepers. After 3 mo of moderate aerobic exercise training, BQ-123 no longer enhanced the vasodilator response to acetylcholine in the short sleepers; thus, reduced ET_A receptor-facilitated ET-1-mediated vasoconstriction represents an important underlying mechanism of the exercise-induced improvement in endothelium-dependent vasodilation. Reduced ET-1 vasoconstriction likely allowed vasodilating factors known to increase with exercise training, such as nitric oxide, to act unopposed, allowing for appropriate vasodilation to acetylcholine observed in the short sleepers after the exercise intervention (14).

The mechanisms by which exercising attenuates the vasomotor function are not yet clear. Elevated oxidative stress and inflammation are associated with a number of sleep disorders including insufficient sleep (43–47). Considering regular aerobic exercise has been shown to decrease both inflammation and oxidative stress (48, 49), it is plausible that these factors could account, in part, for the improvement in vasomotor function.

From a clinical perspective, the value of nightly sleep quantity and quality is increasingly viewed as an important lifestyle factor contributing to both health and disease. There has been a steady rise in the number of adults in the United States reporting short nightly sleep duration (<7 h/night), from ∼22% in 1977 to ∼40% in 2009 (1, 60). With no expected increase in nightly sleep duration, mitigating the negative effects of insufficient sleep (in lieu of changing sleep behavior) has important health implications. The results of the present study demonstrate that regular aerobic exercise can counteract endothelial vasomotor dysfunction associated with insufficient sleep, thus conferring important cardioprotective benefit. It is important to emphasize that our results were accomplished independent of changes in nightly sleep duration and with a home-based, moderate-intensity, aerobic exercise training program that can be safely performed by most, if not all, sedentary otherwise healthy adults. Given that short sleep duration is also associated with an increased prevalence of elevated blood pressure, dyslipidemia, and diabetes (50), regular aerobic exercise may also be efficacious in alleviating this risk burden in short sleepers.

There are a few experiment limitations that should be mentioned. First, the lack of a nonexercising control group is a shortcoming of our study design. However, the 3-mo, home-based aerobic exercise training program used in the present study has been repeatedly shown to improve endothelium-dependent vasodilation and reduce ET-1-mediated vasoconstrictor tone in healthy adult humans varying in age, body composition, and CVD risk (13, 14, 18, 20). Thus, we are confident that the exercise-induced changes in both endothelial vasodilation and vasoconstriction as well as the interaction between the two vasomotor functions were indeed a primary effect of the exercise intervention and not due to chance or experimental bias. Second, we assessed habitual sleep duration by questionnaire without verification by either actigraphic or overnight laboratory monitoring. However, previous studies have demonstrated a strong correlation between self-reported sleep duration and actigraphic data (51, 52). In addition, self-reported sleep duration has been used to accurately and effectively assess the relation between habitual sleep duration and cardiometabolic risk across various populations (6, 8, 23–25, 53). Third, although we screened for sleep disorder breathing (i.e., obstructive sleep apnea) via a questionnaire, the study did not involve overnight laboratory sleep assessment, but in consideration that the majority of subjects were nonobese, the risk of sleep apnea is small (54). Finally, although sleep duration was not affected by the exercise intervention, we did not assess sleep quality. A number of studies have reported that moderate-intensity exercise improves sleep quality (55–58). In addition, there is evidence to suggest that improving sleep quality beneficially affects endothelium-dependent vasodilation (55, 59). Thus, it is possible that exercise-induced improvements in sleep quality may have contributed to our findings.

In conclusion, the results of the present study provide further evidence that insufficient sleep is associated with endothelial vasomotor dysfunction. Diminished endothelium-dependent vasodilation and increased ET-1 mediated vasoconstrictor tone are primary factors underlying CVD risk, development, and severity (36, 40–42). Importantly, endothelial vasomotor dysfunction is not an irreversible consequence of insufficient sleep. Regular aerobic exercise, independent of changes in nightly sleep duration, can significantly enhance endothelial vasomotor function and reduce ET-1-mediated vasoconstriction in adults who sleep <7 h/night. Exercise-induced improvement in endothelium-dependent vasodilation and reduction in ET-1-mediated vasoconstrictor tone may help to alleviate the CVD risks associated with insufficient sleep.

GRANTS

This study was supported by National Heart, Lung, and Blood Institute Grants HL131458 and HL135598 and National Center for Advancing Translational Sciences Grant UL1 TR001082.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

C. DeSouza conceived and designed research; K.A.S., A.R.B., C. Dow, K.J.D., J.J.G., B.L.S., and C. DeSouza performed experiments; K.A.S., A.R.B., K.J.D., J.J.G., and C. DeSouza analyzed data; K.A.S., A.R.B., J.J.G., B.L.S., and C. DeSouza interpreted results of experiments; K.A.S. and J.J.G. prepared figures; K.A.S., B.L.S., and C. DeSouza drafted manuscript; K.A.S. and C. DeSouza edited and revised manuscript; K.A.S., A.R.B., C. Dow, K.J.D., J.J.G., B.L.S., and C. DeSouza approved final version of manuscript.