Regular aerobic exercise counteracts endothelial vasomotor dysfunction associated with insufficient sleep.

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 (ETA 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 ETA 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.

Insufficient sleep is associated with a pro-atherogenic circulating microRNA signature.

NEW FINDINGS: What is the central question of the study Is habitual short sleep associated with altered circulating levels of specific inflammation- and vascular-related microRNAs? What is the main finding and its importance? Circulating levels of miR-125a, miR-126 and miR-146a were significantly lower in the short sleep compared with the normal sleep group. Altered circulating profiles of these vascular-related microRNAs have been linked to vascular inflammation, dysfunction and increased cardiovascular disease events. Sleep-related changes in these microRNAs are consistent with, and might play a role in, the aberrant vascular physiology and increased vascular risk associated with short sleep. ABSTRACT: Habitual short sleep duration (<7 h night-1 ) is associated with increased morbidity and mortality attributable, in large part, to increased inflammatory burden and endothelial dysfunction. MicroRNAs (miRNAs) play a key role in regulating vascular health, and circulating levels are now recognized to be sensitive and specific biomarkers of cardiovascular function, inflammation and disease.  The aim of this study was to determine whether the expression of circulating miR-34a, miR-92a, miR-125a, miR-126, miR-145, miR-146a and miR-150 is disrupted in adults who habitually sleep <7 h night-1 (short sleep). These were chosen based upon their well-established links with vascular inflammation, function and, in turn, cardiovascular risk. Twenty-four adults were studied: 12 with normal nightly sleep duration (six men and six women; age, 55 ± 3 years old; sleep duration, ≥7.0 h night-1 ) and 12 with short nightly sleep duration (seven men and five women; 55 ± 2 years old; sleep duration, <7 h night-1 ), and circulating miRNA expression was assayed by RT-PCR. All subjects were non-smokers, normolipidaemic, non-medicated and free of overt cardiovascular disease. Circulating levels of miR-125a (3.07 ± 1.98 versus 7.34 ± 5.34 a.u.), miR-126 [1.28 (0.42-2.51) versus 1.78 (1.29-4.80) a.u.] and miR-146a [2.55 (1.00-4.80) versus 6.46 (1.50-11.44) a.u.] were significantly lower (∼60, 40 and 60%, respectively) in the short compared with the normal sleep group. However, there were no significant group differences in circulating levels of miR-34a, miR-92a, miR-145 and miR-150. In summary, chronic short sleep is associated with a marked reduction in circulating levels of miR-125a, miR-126 and miR-146a. Dysregulation of these miRNAs might contribute to the increased inflammatory burden and endothelial dysfunction associated with habitual insufficient sleep.

Effects of endothelin-1 on endothelial progenitor cell function.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) contribute to vascular endothelial repair. Endothelin (ET)-1 is associated with endothelial damage and atherogenesis. The experimental aim of this study was to determine, in vitro, the effects of ET-1 on the ability of EPCs to form colonies, migrate, release angiogenic growth factors and resist apoptosis. METHODS: Peripheral blood samples were collected from 10 healthy adult humans. Cells with phenotypic EPC characteristics were isolated and EPC colony-forming capacity (CFU assay), migratory activity (Boyden chamber), release of angiogenic growth factors (enzyme immunoassay) and apoptosis (TUNEL assay) were determined in the absence and presence of ET-1 (100 pmol). RESULTS: EPC colony-forming units (42±12 vs. 39±11), migratory capacity (910±146 vs. 936±148 AU) and release of vascular endothelial growth factor (202.8±68.1 vs. 204.8±69.8 pg/mL) and granulocyte-colony stimulating factor (1294.4±378.3 vs. 1136.1±310.3 pg/mL) were not significantly affected by ET-1. EPCs treated with ET-1 demonstrated a 20% increase (p<0.05) in cellular apoptosis. The proapoptotic effect of ET-1 was abolished with ET receptor blockade as well as with apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) inhibitor. CONCLUSIONS: These results indicate that ET-1 does not affect EPC colony formation, migratory capacity or angiogenic growth factor release, but does increase EPC susceptibility to apoptosis through an NADPH-dependent mechanism. Increased EPC apoptosis may contribute to the proatherogenic effects of ET-1.

CD31+ T cells, endothelial function and cardiovascular risk.

Deficits in endothelial cell repair mechanisms are thought to contribute to the aetiology of endothelial dysfunction and, subsequently, cardiovascular disease (CVD). CD31(+) T cells or so-called "angiogenic T cells" are a newly defined T cell subset that exhibit favourable vascular qualities and show a strong negative relation with atherosclerotic disease severity. Despite growing evidence that CD31(+) T cells are important for vascular homeostasis, it is currently unknown if CD31(+) T cell number and function are related to endothelial function and CVD risk in healthy adults. To address this question, we studied 24 healthy adult men (ages: 21-70). Endothelial function was assessed by the forearm blood flow (FBF) response to intra-arterial infusion of acetylcholine (ACh) and CVD risk was estimated by Framingham Risk Score (FRS). CD31(+) T cell number was determined by fluorescence-activated cell sorting. Magnetic-activated cell sorting was used to isolate CD31(+) T cells for Boyden chamber migration. No relation was observed between CD31(+) T cell number and FBF response to ACh or FRS. However, CD31(+) T cell migration to stromal cell-derived factor (SDF)-1α and vascular endothelial growth factor (VEGF) was positively correlated with FBF response to ACh (r = 0.43 for SDF-1α; r = 0.38 for VEGF; both P<0.05) and inversely related to FRS (r = -0.53 for SDF-1α; r = -0.48 for VEGF; both P<0.05). These findings demonstrate that CD31(+) T cell function, but not number, is associated with in vivo endothelial function and CVD risk in healthy adult men.

Influence of Overweight and Obesity on Circulating Inflammation-Related microRNA.

BACKGROUND: Increased cardiovascular disease risk and prevalence associated with overweight and obesity is due, in part, to heightened inflammatory burden. The mechanisms underlying adiposity-related amplification of inflammation are not fully understood. Alterations in regulators of inflammatory processes such as microRNAs (miRs), however, are thought to play a pivotal role. OBJECTIVE: The aim of this study was to determine the influence of overweight and obesity, independent of other cardiovascular risk factors, on circulating expression of miR-34a, miR-126, miR-146a, miR-150 and miR-181b. METHODS: Forty-five sedentary, middle-aged (47-64 years) adults were studied: 15 were normal weight (8M/7F; BMI: 23.3 ± 0.3 kg/m2); 15 were overweight (8M/7F; 28.2 ± 0.3 kg/m2); and 15 were obese (7M/8F; 32.3 ± 0.5 kg/m2). All subjects were non-smokers, normotensive and free of overt cardiometabolic disease. Circulating levels of the following inflammation-related miRs: miR-34a, miR-126, miR-146a, miR-150 and miR-181b were determined in plasma using standard RT-PCR techniques. miR expression was normalized to exogenous C. elegans miR-39 and reported as relative expression (AU). RESULTS: Circulating miR-34a was ~200% higher (P< 0.05) in the obese as compared with normal weight and overweight groups. Whereas, miR-126, miR-146a and miR-150 were significantly lower (~65%) in both the obese and overweight groups than the normal weight group. There were no significant group differences in circulating expression of miR-181b. miR-34a was positively related (r = 0.43; P< 0.05); whereas, miR-126 (r = -0.48), miR-146a (r = -0.33) and miR-150 (r = -0.43) levels were significantly inversely related to BMI. CONCLUSION: Overweight and obesity, independent of other cardiometabolic risk factors, negatively influences circulating inflammation-related miRs. Dysregulation of circulating miRs may contribute mechanistically to the heightened inflammatory state associated with overweight and obesity.

Association between hypertension and circulating vascular-related microRNAs.

microRNAs (miRNAs) have a key role in regulating inflammation, vascular health and in turn, cardiovascular disease. Specifically, altered circulating expression of miR-17, miR-21, miR-34a, miR-92a, miR-126, miR-145, miR-146a, and miR-150 has been linked with the pathogenesis and progression of cardiovascular disease. The aim of this study was to determine whether the circulating profile of these vascular-related miRNAs is disrupted with hypertension. Thirty sedentary, middle-aged adults were studied: 15 normotensive (10M/5F; age: 56 ± 1 year; BP: 113/71 ± 2/1 mmHg) and 15 hypertensive (10M/5F; 56 ± 2 year; 140/87 ± 2/2 mmHg). All subjects were non-obese and free of other cardiometabolic disorders. Circulating miRNAs were determined in plasma using standard RT-PCR techniques with miRNA primers of interest. Expression was normalized to exogenous C. elegans miR-39 and reported as relative expression in arbitrary units (AU). Circulating expression of miR-34a (9.18 ± 0.94 vs 5.33 ± 0.91 AU) was higher (~170%; P < 0.01) whereas the expression of miR-21 (1.32 ± 0.25 vs 2.50 ± 0.29 AU), miR-126 (0.85 ± 0.10 vs 1.74 ± 0.27 AU) and miR-146a (1.50 ± 0.20 vs 3.10 ± 0.50 AU) were markedly lower (~50%, ~55%, and ~55% respectively; P < 0.05) in the hypertensive vs normotensive groups. Moreover, circulating levels of miR-34a, miR-21, and miR-126 were significantly related to systolic blood pressure (r = 0.48, r = -0.38; r = -0.48); whereas, miR-146a was significantly related to both systolic (r = -0.58) and diastolic (r = -0.55) blood pressure. There were no significant group differences in circulating miR-17, miR-92a, miR-145, and miR-150. In summary, these results suggest that hypertension, independent of other cardiometabolic risk factors, adversely affects the circulating profile of a subset of vascular-related miRNAs that have been link to CVD risk and development.

Insufficient sleep is associated with impaired nitric oxide-mediated endothelium-dependent vasodilation.

BACKGROUND AND AIMS: Habitual short nightly sleep duration is associated with increased atherosclerotic cardiovascular disease risk and morbidity. Vascular endothelial dysfunction represents an important mechanism that may underlie this heightened cardiovascular risk. Impaired endothelium-dependent vasodilation, particularly NO-mediated vasodilation, contributes to the development and progression of atherosclerotic vascular disease and acute vascular events. We tested the hypothesis that chronic insufficient sleep is associated with impaired NO-mediated endothelium-dependent vasodilation in middle-aged adults. METHODS: Thirty adult men were studied: 15 with normal nightly sleep duration (age: 58 ± 2 y; sleep duration: 7.7 ± 0.2 h/night) and 15 with short nightly sleep duration (55 ± 2 y; 6.1 ± 0.2 h/night). Forearm blood flow (FBF) responses to intra-arterial infusion of acetylcholine, in the absence and presence of the endothelial NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA), as well as responses to sodium nitroprusside, were determined by strain-gauge venous occlusion plethysmography. RESULTS: The FBF response to acetylcholine was lower (∼20%; p<0.05) in the short sleep duration group (from 4.6 ± 0.3 to 11.7 ± 1.0 ml/100 ml tissue/min) compared with normal sleep duration group (from 4.4 ± 0.3 to 14.5 ± 0.5 ml/100 ml tissue/min). L-NMMA significantly reduced the FBF response to acetylcholine in the normal sleep duration group (∼40%), but not the short sleep duration group. There were no group differences in the vasodilator response to sodium nitroprusside. CONCLUSIONS: These data indicate that short nightly sleep duration is associated with endothelial-dependent vasodilator dysfunction due, in part, to diminished NO bioavailability. Impaired NO-mediated endothelium-dependent vasodilation may contribute to the increased cardiovascular risk with insufficient sleep.

Nebivolol, But Not Metoprolol, Treatment Improves Endothelial Fibrinolytic Capacity in Adults With Elevated Blood Pressure.

BACKGROUND: Vascular endothelial fibrinolytic function is impaired in adults with prehypertension and hypertension and plays a mechanistic role in the development of atherothrombotic events. The influence of ß-blockers on endothelial fibrinolysis is unknown. This study compared the effects of chronic nebivolol and metoprolol treatment on endothelial tissue-type plasminogen activator (t-PA) release in adults with elevated blood pressure (BP). METHODS AND RESULTS: Forty-four middle-aged adults (36% women) with elevated BP completed a 3-month, double-blind, randomized, placebo-controlled trial comparing nebivolol (5 mg/d), metoprolol succinate (100 mg/d), and placebo. Net endothelial t-PA release was determined in vivo in response to intrabrachial infusions of bradykinin and sodium nitroprusside before and after each intervention. In a subset, the dose-response curves to bradykinin and sodium nitroprusside were repeated with a coinfusion of the antioxidant vitamin C. At baseline, resting BP and endothelial t-PA release were comparable between the 3 groups. BP decreased to a similar extent (≈10 mm Hg) in the nebivolol- and metoprolol-treated groups. There was a substantial increase (≈30%; P<0.05) in the capacity of the endothelium to release t-PA following chronic treatment with nebivolol but not metoprolol or placebo. Mitigating oxidant stress with vitamin C coinfusion potentiated t-PA release (90%; P<0.05) at baseline in all groups. However, after the intervention, t-PA release was unchanged by vitamin C coinfusion in the nebivolol group only. CONCLUSIONS: Nebivolol but not metoprolol improves endothelial t-PA release in adults with elevated BP. This may be an important vascular benefit of nebivolol. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01595516.

Chronic Nebivolol Treatment Suppresses Endothelin-1-Mediated Vasoconstrictor Tone in Adults With Elevated Blood Pressure.

UNLABELLED: Endothelin-1 (ET-1) plays a major role in the pathophysiology of hypertension and its associated cardiovascular risk. We tested the hypothesis that chronic nebivolol treatment reduces ET-1-mediated vasoconstrictor tone in adult humans with elevated blood pressure (BP). Furthermore, reducing ET-1 vasoconstrictor activity contributes to the improvement in endothelial vasodilator function associated with nebivolol treatment. Forty-two middle-aged adults with elevated BP (systolic BP ≥130 mm Hg or diastolic BP ≥85 mm Hg) completed a 3-month, double-blind, randomized, placebo controlled trial: 14 received nebivolol (8 men/6 women; 5 mg per day); 14 received metoprolol succinate (9 men/5 women; 100 mg per day); and 14 received placebo (9 men/5 women). Forearm blood flow (plethysmography) responses to selective (BQ-123: 100 nmol/min; 60 minutes) and nonselective (BQ-123+BQ-788 [50 nmol/min]; 60 minutes) ET-1 receptor blockade, as well as acetylcholine (4.0, 8.0, and 16.0 µg per 100 mL of tissue per minute) in the absence and presence of nonselective ET-1 receptor blockade were determined before and after each treatment intervention. Forearm blood flow responses to BQ-123 and BQ-123+BQ-788 were similarly and significantly elevated (≈30% and 60%, respectively) from baseline in all 3 groups. Nebivolol, but not metoprolol or placebo, therapy resulted in a marked (≈25% and 45%; P<0.05) reduction in forearm blood flow response to BQ-123 and BQ-123+BQ-788. Moreover, after nebivolol therapy only, vasodilator response to acetylcholine was not significantly increased by ET-1 receptor blockade. These results demonstrate that nebivolol, but not metoprolol, treatment reduces ET-1-mediated vasoconstrictor tone in adult humans with elevated BP. In addition, nebivolol-induced reduction in ET-1-mediated vasoconstrictor tone underlies the favorable effects of this ß-blocker on endothelial vasodilation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01395329.

ENDOTHELIN-1 SYTEM ACTIVITY IN ADULTS WITH BORDERLINE HIGH LDL-CHOLESTEROL.

BACKGROUND: Modest elevations in plasma low-density lipoprotein (LDL)-cholesterol have been shown to confer a significant increase in cardiovascular risk. Endothelin (ET)-1 is a vasoconstrictor peptide with proatherogenic properties. The experimental aim of this study was to determine whether ET-1 system activity is elevated in adults with borderline high LDL-cholesterol, independent of other cardiometabolic abnormalities. METHODS: Forearm blood flow (FBF; plethysmography) responses to intra-arterial infusion of ET-1, selective ETA receptor blockade (BQ-123), and non-selective ETA/B blockade (BQ-123 + BQ-788) were determined in 40 middle-aged and older adults (45-70 years): 20 with optimal/near optimal LDL-cholesterol (<3.4 mmol/L) and 20 with borderline-high LDL-cholesterol (3.4-4.1 mmol/L). RESULTS: Both groups demonstrated a similar, non-significant (~10%) reduction in FBF to ET-1. BQ-123 and BQ-123+788 elicited a modest, but significant, increase in FBF (~15-20%) in each group. However, there were no group differences in the FBF responses to either selective ETA or non-selective ETA/B receptor antagonism. CONCLUSION: Borderline-high LDL-C is not associated with increased ET-1 mediated vasoconstrictor tone. Disrupted ET-1 system activity may not contribute to the increased cardiovascular risk burden with borderline-high LDL-cholesterol.

Impaired fasting blood glucose is associated with increased endothelin-1 vasoconstrictor tone.

AIM/HYPOTHESIS: The experimental aim of this study was to determine whether ET-1-mediated vasoconstrictor tone is elevated in adult humans with impaired fasting blood glucose concentrations, independent of other cardiovascular risk factors. METHODS: Forearm blood flow (FBF: plethysmography) responses to intra-arterial infusion of selective ETA receptor blockade (BQ-123: 100 nmol/min for 60 min) and non-selective ETA/B blockade (BQ-123 + BQ-788: 50 nmol/min for 60 min) were determined in 28 middle-aged, sedentary adults (17 M/11 F): 14 with normal fasting blood glucose (age: 57 ± 2 yr; 6 F/8 M; BMI: 29.2 ± 0.9 kg/m(2); glucose: 4.9 ± 0.1 mmol/L) and 14 impaired fasting blood glucose (58 ± 1 yr; 5 F/9 M; 29.6 ± 1.1 kg/m(2); 5.8 ± 0.1 mmol/L) concentrations. RESULTS: Selective ETA receptor blockade elicited a significantly greater (∼20%) increase in FBF in the impaired fasting glucose adults compared with the normoglycemia controls. ETA/B blockade resulted in a further 2-fold increase (P < 0.05) in FBF above that elicited by ETA receptor antagonism in the impaired fasting glucose but not normal fasting glucose adults. There was a positive correlation between fasting blood glucose levels and the peak vascular responses to ETA (r = 0.44; P < 0.05) and ETA/B (r = 0.62; P < 0.05) blockade. No other anthropometric, hemodynamic or metabolic variable was correlated with the blood flow responses to ET-1 receptor blockade. CONCLUSIONS/INTERPRETATION: ET-1-mediated vasoconstrictor tone is elevated in adults with impaired fasting blood glucose concentrations, independent of other cardiometabolic risk factors. Enhanced ET-1 system activity may underlie endothelial vasomotor dysfunction and increased cardiovascular risk in adults with impaired fasting blood glucose concentrations.

Nitric oxide-mediated endothlium-dependent vasodilation is impaired with borderline high-LDL cholesterol.

The experimental aims of this study were to determine: (1) whether nitric oxide-mediated endothelium-dependent vasodilation is blunted in adult humans with borderline high plasma low-density lipoprotein (LDL)-cholesterol compared with adults with optimal/near optimal LDL-cholesterol levels; and, if so: (2) whether the magnitude of impairment in adults with borderline high LDL-cholesterol is similar to adults with high LDL-cholesterol. Forearm blood flow responses to intraarterial infusions of acetylcholine and sodium nitroprusside were measured in 50 middle-aged (43-64 year) adults: 20 in the optimal/near optimal LDL-cholesterol range (<130 mg/dL); 20 with borderline high LDL-cholesterol (130-159 mg/dL); and 10 with high LDL-cholesterol ($160 mg/dL). In addition, blood flow responses to acetylcholine were determined in the absence and presence of the endothelial nitric oxide synthase inhibitor N(G) -monomethyl-L-arginine (L-NMMA). Vasodilation to acetylcholine was ~20% lower (p < 0.05) in the borderline high (from 4.3 ± 0.2 to 12.3 ± 0.8 mL/100 mL tissue/min) and high (from 4.3 ± 0.3 to 12.0 ± 0.5 mL/100 mL tissue/min) LDL-cholesterol groups compared with the optimal/near optimal (from 4.4 ± 0.2 to 14.5 ± 0.5 mL/100 mL tissue/min) LDL-cholesterol group. L-NMMA significantly reduced (~30%) the vasodilator response to acetylcholine in the optimal/near optimal LDL-cholesterol group but not the borderline high or high LDL-cholesterol groups. Borderline high LDL-cholesterol is associated with impaired nitric oxide-mediated endothelium-dependent vasodilation.

White blood cell count and endothelin-1 vasoconstrictor tone in middle-aged and older adults.

BACKGROUND: Higher white blood cell (WBC) count is associated with impaired endothelium-dependent vasodilation. However, the influence of higher WBC count on endothelin (ET)-1 vasoconstrictor activity is currently unknown. We tested the hypothesis that adults with elevated WBC count demonstrate enhanced ET-1 system activity. METHODS: Thirty-four healthy adults were studied: 17 with WBC count < 5.0 × 109 cells/L (lower WBC; 9M/8F; age: 53 ± 2 yr) and 17 with WBC count > 5.0 × 109 cells/L (higher WBC; 10M/7F; 54 ± 3 yr). Forearm blood flow (FBF) responses to intra-brachial infusion of ET-1 (5 pmol/min for 20 min) and selective ETA receptor blockade (BQ-123; 100 nmol/min for 60 min) were measured by venous occlusion plethysmography. RESULTS: The vasoconstrictor response to ET-1 was significantly blunted (∼60%) in the higher WBC group versus the lower WBC group. The FBF responses to selective ETA receptor blockade were also significantly different (P < 0.05) between the groups. In the lower WBC group, resting FBF increased marginally (∼5%) to BQ-123, whereas the increase in FBF to BQ-123 was significantly greater (∼15%) in higher WBC group. Furthermore, there was a significant relation between WBC count and FBF response to ET-1 (r = -0.43) and BQ-123 (r = 0.41). CONCLUSIONS: Relative elevations in WBC count in middle-aged and older adults, independent of adiposity and other cardiometabolic risk factors, are associated with enhanced ET-1-mediated vasoconstrictor tone. Elevated ET-1 system activity may be a mechanism linking higher WBC count with increased cardiovascular risk.

Human aging and CD31+ T-cell number, migration, apoptotic susceptibility, and telomere length.

CD31(+) T cells, or so-called "angiogenic T cells," have been shown to demonstrate vasculoprotective and neovasculogenic qualities. The influence of age on CD31(+) T-cell number and function is unclear. We tested the hypothesis that circulating CD31(+) T-cell number and migratory capacity are reduced, apoptotic susceptibility is heightened, and telomere length is shortened with advancing age in adult humans. Thirty-six healthy, sedentary men were studied: 12 young (25 ± 1 yr), 12 middle aged (46 ± 1 yr), and 12 older (64 ± 2 yr). CD31(+) T cells were isolated from peripheral blood samples by magnetic-activated cell sorting. The number of circulating CD31(+) T cells (fluorescence-activated cell sorting analysis) was lower (P < 0.01) in older (24% of CD3(+) cells) compared with middle-aged (38% of CD3(+) cells) and young (40% of CD3(+) cells) men. Migration (Boyden chamber) to both VEGF and stromal cell-derived factor-1α was markedly blunted (P < 0.05) in cells harvested from middle-aged [306.1 ± 45 and 305.6 ± 46 arbitrary units (AU), respectively] and older (231 ± 65 and 235 ± 62 AU, respectively) compared with young (525 ± 60 and 570 ± 62 AU, respectively) men. CD31(+) T cells from middle-aged and older men demonstrated greater apoptotic susceptibility, as staurosporine-stimulated intracellular caspase-3 activation was ∼ 40% higher (P < 0.05) than young. There was a progressive age-related decline in CD31(+) T-cell telomere length (young: 10,706 ± 220 bp; middle-aged: 10,179 ± 251 bp; and older: 9,324 ± 192 bp). Numerical and functional impairments in this unique T-cell subpopulation may contribute to diminished angiogenic potential and greater cardiovascular risk with advancing age.