Christopher A DeSouza

University of Colorado, Denver, Colorado, United States

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Publications (116)453.58 Total impact

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    ABSTRACT: 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.
    Artery Research 09/2014;
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    ABSTRACT: Approximately 50% of middle-aged and older adults in the United States regularly consume a diet high in saturated fat. High dietary saturated fat intake has been linked to promote atherothrombotic vascular disease. We tested the hypothesis that endothelial fibrinolytic function is diminished in middle-aged and older adults who habitually consume a diet high in saturated fat. Twenty-four healthy, sedentary middle-aged, and older adults (54 to 71 years) were studied: 10 (8 men and 2 women) with a dietary saturated fat intake <10% (lower saturated fat) of total calories and 14 (9 men and 5 women) with a dietary saturated fat intake ≥10% of total calories (high saturated fat). Net endothelial release of tissue-type plasminogen activator (t-PA), the primary activator of fibrinolysis, was determined, in vivo, in response to intrabrachial infusions of bradykinin (12.5 to 50.0 ng/100 ml tissue/min) and sodium nitroprusside (1.0 to 4.0 μg/100 ml tissue/min). Capacity of the endothelium to release t-PA in response to bradykinin was ∼30% less (p <0.05) in the high (from -0.7 ± 0.6 to 36.9 ± 3.3 ng/100 ml tissue/min) compared with the lower (from -0.3 ± 0.3 to 53.4 ± 7.8 ng/100 ml tissue/min) dietary saturated fat group. Moreover, total amount of t-PA released was significantly less (∼30%) (201 ± 22 vs 274 ± 29 ng/100 ml tissue) in the adults who reported consuming a diet high in saturated fat. These results indicate that the capacity of the endothelium to release t-PA is lower in middle-aged and older adults who habitually consume a diet high in saturated fat. In conclusion, endothelial fibrinolytic dysfunction may underlie the increased atherothrombotic disease risk with a diet high in saturated fat.
    The American Journal of Cardiology 06/2014; · 3.21 Impact Factor
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    ABSTRACT: In vitro, C-reactive protein (CRP) impairs endothelial progenitor cell (EPC) function; however, the influence of CRP on EPCs in vivo is unclear. We determined whether EPC function is impaired in adults with elevated plasma CRP concentrations, independent of other risk factors. EPCs were harvested from 75 adults (43 males, 32 females): 25 with low CRP (<1.0 mg/L); 25 with moderate CRP (1.0-3.0 mg/L); and 25 with high CRP (>3.0 mg/L). The capacity of EPCs to form colonies (colony assay), migrate (Boyden chamber), release angiogenic growth factor (ELISA) and resist apoptosis (active caspase-3) was determined. There were no significant differences between the CRP groups in EPC colony formation (CFU), migration (AU) or the ability to release vascular endothelial growth factor (VEGF; pg/mL): low (13 ± 3 CFU; 1255 ± 100 AU; 126 ± 24 pg/mL); moderate (11 ± 3 CFU; 1137 ± 85 AU; 97 ± 14 pg/mL); and high (13 ± 4 CFU; 1071 ± 80 AU; 119 ± 22 pg/mL) CRP. Staurosporine-stimulated activation of caspase-3 was also similar between the low (2.3 ± 0.2 ng/mL), moderate (2.1 ± 0.3 ng/mL), and high (2.2 ± 0.2 ng/mL) CRP groups. These results indicate that elevations in plasma CRP are not associated with impaired EPC function. EPC dysfunction may not play a role in CRP-related cardiovascular risk.
    Clinical and Translational Science 01/2014; · 2.33 Impact Factor
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    ABSTRACT: Objective To determine whether endothelin (ET)-1 vasoconstrictor tone is greater in overweight and obese adults with the metabolic syndrome (MetS). Materials/Methods Forty overweight/obese middle-aged and older adults (age: 43-71 years; BMI: 25.1-36.9 kg/m2) were studied: 20 without MetS (13 M/7 F) and 20 with MetS (13 M/7 F). MetS was established according to NCEP ATP III guidelines. 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 receptor blockade (BQ-123 + BQ-788 [50 nmol/min for 60 min]) were determined. Results In response to the selective ETA antagonism, there was a significant increase in forearm blood flow from baseline in both groups. However, the increase in forearm blood flow was significantly higher (P = 0.03; ~ 45%) in the overweight/obese group with MetS than the group without MetS. In contrast, there were no significant group differences in FBF responses to non-selective ETA/B receptor blockade. Peak vasodilator responses to nonselective ETA/B blockade were ~ 50% higher than baseline blood flow in the overweight/obese groups without and with MetS. Conclusion MetS is associated with higher ET-1 vasoconstrictor tone in overweight/obese adults. The enhanced ET-1 vasoconstrictor activity with MetS is mediated by the ETA receptor subtype.
    Metabolism. 01/2014;
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    ABSTRACT: 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.
    Atherosclerosis 04/2013; · 3.71 Impact Factor
  • Brian R Weil, Jared J Greiner, Brian L Stauffer, Christopher A Desouza
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    ABSTRACT: STUDY OBJECTIVES: Habitual short sleep duration is associated with increased cardiovascular disease morbidity and mortality resulting from atherothrombotic events. The mechanisms responsible for this heightened cardiovascular risk are not fully understood. The capacity of the endothelium to release tissue-type plasminogen activator (t-PA), the primary activator of the fibrinolytic system, is a key endogenous defense mechanism against intravascular fibrin deposition and thrombosis. We tested the hypothesis that endothelial t-PA release is impaired in adults who sleep less than 7 h/night compared with adults who sleep between 7 and 9 h/night. DESIGN: THIRTY ADULT MEN WERE STRATIFIED BASED ON AVERAGE NIGHTLY HABITUAL SLEEP DURATION: 15 with normal sleep duration (age: 55 ± 2 years; sleep duration: 7.6 h/night) and 15 with short sleep duration (56 ± 2 years; 6.1 h/night). Net endothelial release of t-PA was determined, in vivo, in response to intra-brachial infusions of bradykinin (12.5-50.0 ng/100 mL tissue/min) and sodium nitroprusside (1.0-4.0 μg/100 mL tissue/min). MEASUREMENTS AND RESULTS: Net endothelial t-PA release to bradykinin was significantly lower (∼25%) in the short (from 0.4 ± 0.8 to 41.5 ± 4.3 ng/100 mL tissue/min) compared with the normal (0.4 ± 0.5 to 64.9 ± 6.7 ng/100 mL/tissue/min) sleep duration group. Furthermore, there was an inverse relation between average nightly sleep duration and peak t-PA release to bradykinin (r = 0.36, P < 0.05). CONCLUSIONS: Endothelial t-PA release is impaired in adults who report short habitual sleep duration. Impaired endothelial fibrinolytic function may underlie the increased atherothrombotic risk associated with chronic short sleep. CITATION: Weil BR; Greiner JJ; Stauffer BL; DeSouza CA. Self-reported habitual short sleep duration is associated with endothelial fibrinolytic dysfunction in men: a preliminary report. SLEEP 2013;36(2):183-188.
    Sleep 01/2013; 36(2):183-188. · 5.10 Impact Factor
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    ABSTRACT: 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. Thirty-four healthy adults were studied: 17 with WBC count < 5.0 × 10(9) cells/L (lower WBC; 9M/8F; age: 53 ± 2 yr) and 17 with WBC count > 5.0 × 10(9) 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. 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). 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.
    Artery Research 06/2012; 6(2):65-70.
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    ABSTRACT: 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.
    Clinical and Translational Science 02/2012; 5(1):21-6. · 2.33 Impact Factor
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    ABSTRACT: Prehypertension (blood pressure [BP] 120-139/80-89 mm Hg) is an independent risk factor for hypertension and cardiovascular disease. Currently, it is unknown whether endothelin (ET)-1-mediated vasoconstrictor tone is elevated with BP in the prehypertensive range. The aims of this study were to determine whether ET-1 vasoconstrictor tone is elevated in prehypertensive adults and, if so, whether ET-1-mediated vasoconstriction contributes to endothelial vasodilator dysfunction in this population. Forearm blood flow responses to selective ET(A) receptor blockade (BQ-123; 100 nmol/min) were determined in 26 normotensive adults (age 55 ± 1 years; BP 112 ± 1/72 ± 1 mm Hg) and 30 prehypertensive adults (57 ± 1 years; BP 130 ± 1/80 ± 1 mm Hg). In a subset of participants, forearm blood flow responses to nonselective ET-1 receptor blockade (BQ-123 + BQ-788) were determined. Endothelium-dependent vasodilation to acetylcholine (8.0-32.0 μg/100 mL tissue/min) was measured in the absence and presence of selective ET(A) receptor blockade. BQ-123 elicited a significantly greater increase in forearm blood flow in prehypertensive (approximately 20%) than in normotensive (approximately 5%) adults. Addition of BQ-788 resulted in a further increase (P < 0.05) in forearm blood flow in prehypertensive but not in normotensive adults. Forearm blood flow responses to acetylcholine were lower (P < 0.05) in prehypertensive (4.6 ± 0.3 to 12.6 ± 0.5 mL/100 mL tissue/min) than in normotensive (4.9 ± 0.3 to 14.7 ± 0.8 mL/100 mL tissue/min) adults. Co-infusion of BQ-123 did not affect acetylcholine-induced vasodilation in normotensive adults but resulted in an approximately 20% increase (P < 0.05) in prehypertensive adults. ET-1-mediated vasoconstrictor tone is elevated with prehypertension, contributing to impaired endothelium-dependent vasodilation. ET-1 vasoconstriction may underlie the increased risk of hypertension and cardiovascular disease in prehypertensive adults.
    The Canadian journal of cardiology 01/2012; 28(3):347-53. · 3.12 Impact Factor
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    ABSTRACT: 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. 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). 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. 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.
    Clinical Chemistry and Laboratory Medicine 01/2012; 50(6):1121-4. · 3.01 Impact Factor
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    Brian R Weil, Jared J Greiner, Christopher A DeSouza, Brian L Stauffer
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    ABSTRACT: Increased plasma concentrations of C-reactive protein (CRP) independently predict future atherothrombotic events in healthy asymptomatic adults. CRP may promote atherothrombosis by altering fibrinolytic balance; however, the influence of increased plasma CRP concentrations on endothelial fibrinolysis in healthy adults is unclear. We tested the hypothesis that endothelial release of tissue-type plasminogen activator (t-PA) is impaired in adults with increased plasma CRP concentrations independent of other cardiometabolic risk factors. Fifty-four healthy adults were studied: 24 with CRP <1.0 mg/L (low CRP; 18 men and 6 women, 55 ± 2 years old), 18 with CRP 1.0 to 3.0 mg/L (moderate CRP; 8 men and 10 women, 58 ± 2 years old), and 12 with CRP >3.0 mg/L (high CRP; 7 men and 5 women, 56 ± 2 years old). Net endothelial release of t-PA was determined in vivo in response to intrabrachial infusions of bradykinin (125 to 500 ng/min) and sodium nitroprusside (2.0 to 8.0 μg/min). Capacity of the endothelium to release t-PA was significantly lower (∼30%) in the high (0.32 ± 0.5 to 38.9 ± 6.0 ng · 100 ml tissue(-1) · min(-1)) and moderate (-0.05 ± 0.4 to 39.3 ± 5.2 ng · 100 ml tissue(-1) · min(-1)) compared to the low (0.42 ± 0.9 to 61.8 ± 5.2 ng · 100 ml tissue(-1) · min(-1)) CRP group. There was no significant difference in t-PA release between the high and moderate CRP groups. Plasma CRP concentrations were inversely related to t-PA release (r = -0.38, p <0.05). In conclusion, these results indicate that the capacity of the endothelium to release t-PA is decreased in adults with plasma CRP ≥1.0 mg/L. Endothelial fibrinolytic dysfunction may underlie the increased atherothrombotic risk associated with increases in plasma CRP concentrations in otherwise healthy adults.
    The American journal of cardiology 09/2011; 108(11):1675-9. · 3.58 Impact Factor
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    ABSTRACT: 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.
    Heart Lung &amp Circulation 07/2011; 20(10):659-62. · 1.25 Impact Factor
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    ABSTRACT: It has been suggested that body fat distribution may be an important determinant of the impact of adiposity on endothelial function. We tested the hypothesis that overweight/obese adults with abdominal adiposity exhibit worse endothelial vasodilator and fibrinolytic function than overweight/obese adults without abdominal adiposity. Sixty adult men were studied: 20 normal weight (BMI: 22.3 ± 0.7 kg/m2; waist circumference (WC): 84.9 ± 2.0 cm); 20 overweight/obese with WC <102 cm (29.2 ± 0.3 kg/m2; 98.1 ± 0.7 cm); and 20 overweight/obese with WC ≥102 cm (30.0 ± 0.4 kg/m2; 106.7 ± 1.0 cm). Forearm blood flow (FBF) responses to intra-arterial acetylcholine and sodium nitroprusside (SNP) were measured. Additionally, net endothelial release of tissue-type plasminogen activator (t-PA) was determined in response to bradykinin (BK) and SNP. Overweight/obese men demonstrated lower (~30%; P < 0.01) FBF responses to acetylcholine compared with normal weight controls. However, there were no differences in FBF responses to acetylcholine between overweight/obese men with (4.1 ± 0.3-10.8 ± 1.3 ml/100 ml tissue/min) and without (4.5 ± 0.3-11.6 ± 0.8 ml/100 ml tissue/min) abdominal adiposity. Similarly, endothelial t-PA release to BK was lower (~40%; P < 0.05) in the overweight/obese men compared with normal weight controls; however, t-PA release was not different between the overweight/obese men with (-0.7 ± 0.4-40.4 ± 6.2 ng/100 ml tissue/min) and without (-0.3 ± 0.6-48 ± 7.5 ng/100 ml tissue/min) abdominal adiposity. These results indicate that abdominal obesity is not associated with greater impairment in endothelial vasodilation and fibrinolytic capacity in overweight/obese men. Excess adiposity, regardless of anatomical distribution pattern, is associated with impaired endothelial function.
    Obesity 07/2011; 19(9):1742-6. · 3.92 Impact Factor
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    ABSTRACT: Endothelin (ET)-1-mediated vasoconstrictor tone contributes to the development and progression of several adiposity-related conditions, including hypertension and atherosclerotic vascular disease. The aims of the present study were to determine 1) whether endogenous ET-1 vasoconstrictor activity is elevated in overweight and obese adults, and, if so, 2) whether increased ET-1-mediated vasoconstriction contributes to the adiposity-related impairment in endothelium-dependent vasodilation. Seventy-nine adults were studied: 34 normal weight [body mass index (BMI) < 25 kg/m(2)], 22 overweight (BMI ≥ 25 and < 30 kg/m(2)), and 23 obese (BMI ≥ 30 kg/m(2)). Forearm blood flow (FBF) responses to intra-arterial infusion of ET-1 (5 pmol/min for 20 min) and selective ET-1 receptor blockade (BQ-123, 100 nmol/min for 60 min) were determined. In a subset of the study population, FBF responses to ACh (4.0, 8.0, and 16.0 μg·100 ml tissue(-1)·min(-1)) were measured in the absence and presence of selective ET-1 receptor blockade. The vasoconstrictor response to ET-1 was significantly blunted in overweight and obese adults (∼ 70%) compared with normal weight adults. Selective ET-1 receptor blockade elicited a significant vasodilator response (∼ 20%) in overweight and obese adults but did not alter FBF in normal weight adults. Coinfusion of BQ-123 did not affect FBF responses to ACh in normal weight adults but resulted in an ∼ 20% increase (P < 0.05) in ACh-induced vasodilation in overweight and obese adults. These results demonstrate that overweight and obesity are associated with enhanced ET-1-mediated vasoconstriction that contributes to endothelial vasodilator dysfunction and may play a role in the increased prevalence of hypertension with increased adiposity.
    AJP Heart and Circulatory Physiology 06/2011; 301(3):H689-95. · 4.01 Impact Factor
  • Brian R Weil, Brian L Stauffer, Jared J Greiner, Christopher A DeSouza
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    ABSTRACT: Endothelial vasodilator dysfunction contributes to the development of hypertension (blood pressure (BP) ≥ 140/90 mm Hg) and cardiovascular disease (CVD). Prehypertension (BP 120-139/80-89 mm Hg) has recently been identified as an independent risk factor for hypertension and CVD. It is currently unclear whether BP in the prehypertensive range is associated with endothelial vasodilator dysfunction. We tested the hypothesis that BP in the prehypertensive range, independent of other cardiovascular risk factors, is associated with impaired nitric oxide (NO)-mediated endothelium-dependent vasodilation. Forearm blood flow (FBF) responses to intra-arterial acetylcholine (ACh; 8.0-32.0 µg/100 ml tissue/min) and sodium nitroprusside (SNP; 1.0-4.0 µg/100 ml tissue/min) were measured in 20 normotensive (age: 56 ± 1 years; BP: 110/70 ± 1/2 mm Hg) and 20 prehypertensive (56 ± 2 years; 128/79 ± 2/2 mm Hg) adults. In addition, FBF responses to ACh were determined in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) (5 mg/min). FBF responses to ACh were significantly lower (~30%) in prehypertensive (from 4.2 ± 0.3 to 11.4 ± 0.7 ml/100 ml tissue/min) compared with normotensive (from 4.6 ± 0.2 to 14.5 ± 0.7 ml/100 ml tissue/min) adults. There were no group differences in FBF responses to SNP. Co-infusion of L-NMMA significantly reduced the FBF response to ACh in the normotensive (~30%; P <0.05) but not the prehypertensive adults. Prehypertension is associated with impaired NO-mediated endothelium-dependent vasodilation. The endothelial vasodilator dysfunction that characterizes hypertension is present at BP levels in the prehypertensive range and may contribute to the increased risk of hypertension and CVD in this population.
    American Journal of Hypertension 06/2011; 24(9):976-81. · 3.67 Impact Factor
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    ABSTRACT: The aim of this study was to determine if aging is associated with enhanced endothelial progenitor cell (EPC) sensitivity to apoptosis. Cells with phenotypic EPC characteristics were isolated from healthy, nonobese young (age 25 ± 1 years) and older (61 ± 1 years) men. Intracellular active caspase-3 concentrations in response to staurosporine stimulation were approximately 35% higher (p < 0.05) in EPCs from older (3.15 ± 0.29 pg/ml) compared with young (2.33 ± 0.24 pg/ml) men. Protein expression of Akt, p70 S6-kinase and Bcl-2 was markedly lower (approx. 35, 75 and 60%, respectively, all p < 0.05) in EPCs from older compared with young men, whereas there were no age-related differences in either 14-3-3ε or Bax expression. Additionally, EPC telomerase activity was 57% lower (p < 0.05) in older (0.18 ± 0.11 AU) versus young (0.43 ± 0.11 AU) men. These results indicate that aging is associated with a proapoptotic EPC phenotype characterized by decreased expression of key antiapoptotic proteins associated with the PI-3-kinase signaling pathway and reduced telomerase activity. These age-related changes likely contribute, in part, to the diminished ability of EPCs to resist an apoptotic stimulus in older men. Increased susceptibility to apoptosis may contribute to the numerical and functional impairments observed in EPCs with aging.
    Journal of Vascular Research 05/2011; 48(5):408-14. · 2.43 Impact Factor
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    ABSTRACT: Chronic short sleep duration has been linked to endothelial dysfunction and increased risk of cardiovascular disease. Circulating endothelial progenitor cells (EPCs) are vital to endogenous vascular repair processes and cardiovascular health. We tested the hypothesis that habitual short sleep duration is associated with impairment in EPC number and function. Cells with phenotypic EPC characteristics were isolated from 37 healthy, sedentary adults: 20 with normal sleep duration (13M/7F; age: 59±1 years; sleep duration: 7.7±0.1 h/night) and 17 with short sleep duration (9M/8F; 56±2 years; 6.0±0.2 h/night). EPC number was assessed by flow cytometric analysis of the percentage of peripheral blood mononuclear cells negative for CD45 and positive for CD34, VEGFR-2, and CD133 antigens. EPC colony-forming capacity was determined by colony-forming unit (CFU) assay; migration by Boyden chamber; and intracellular caspase-3 concentrations by immunoassay. There were no significant differences between groups in EPC number (0.001±0.0004 vs. 0.001±0.0003 %), colony-forming capacity (6.1±1.5 vs. 5.4±1.7 CFUs), or migration to VEGF (1410.1±151.2 vs. 1334.3±111.1 AU). Furthermore, there were no group differences in basal and staurosporine-stimulated intracellular concentrations of active caspase-3 (0.3±0.03 vs. 0.5±0.1 ng/mL; and 2.9±0.4 vs. 2.7±0.3 ng/mL), a marker of apoptotic susceptibility. Taken together, these data indicate that short sleep duration is not associated with EPC dysfunction in healthy adults. Numerical and functional impairment in circulating EPCs may not contribute to the increased cardiovascular risk with habitual short sleep duration.
    Journal of cardiovascular disease research 04/2011; 2(2):110-4.
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    ABSTRACT: ET (endothelin)-1, a potent vasoconstrictor peptide released by the endothelium, plays an important role in vasomotor regulation and has been linked to diminished endothelial vasodilator capacity in several pathologies associated with human aging, including hypertension, Type 2 diabetes and coronary artery disease. However, it is currently unknown whether the decline in endothelial vasodilatation with advancing age is due to elevated ET-1 vasoconstrictor activity. Accordingly, we tested the hypothesis that the age-related impairment in ACh (acetylcholine)-mediated endothelium-dependent vasodilatation is due, at least in part, to increased ET-1-mediated vasoconstrictor tone. FBF (forearm blood flow) responses to ACh, SNP (sodium nitroprusside) and BQ-123 (ET(A) receptor blocker) were determined in 14 young (age, 25 ± 1 years) and 14 older (age, 61 ± 2 years) healthy non-obese men. Additionally, FBF responses to ACh were determined in the presence of ETA blockade. Vasodilatation to ACh was lower (approx. 25%; P<0.05) in the older men (from 4.9 ± 0.2 to 13.9 ± 0.9 ml·100 ml(-1) of tissue·min(-1)) compared with the young men (4.6 ± 0.3 to 17.2 ± 1.0 ml·100 ml(-1) of tissue·min(-1)). There were no differences in FBF responses to SNP between the young (4.8 ± 0.3 to 18.5 ± 0.3 ml·100 ml(-1) of tissue·min(-1)) and older (5.1 ± 0.3 to 17.3 ± 0.8 ml·100 ml(-1) of tissue·min(-1)) men. In the young men, resting FBF was not significantly altered by BQ-123, whereas, in the older men, FBF increased approx. 25% in response to BQ-123 infusion (P<0.05). Co-infusion of ACh with BQ-123 resulted in an approx. 20% increase in the ACh-induced vasodilatation in older men compared with saline. In contrast, FBF responses to ACh were not significantly altered by ET(A) blockade in the young men. In conclusion, these results demonstrate that ET-1 vasoconstrictor activity contributes, at least in part, to diminished endothelium-dependent vasodilatation in older men.
    Clinical Science 02/2011; 120(11):485-91. · 4.86 Impact Factor
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    Owen J MacEneaney, Elizabeth Connick, Christopher A DeSouza
    JAIDS Journal of Acquired Immune Deficiency Syndromes 02/2011; 56(2):e49-50. · 4.65 Impact Factor
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    ABSTRACT: 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.
    Journal of Applied Physiology 12/2010; 109(6):1756-61. · 3.48 Impact Factor

Publication Stats

3k Citations
453.58 Total Impact Points

Institutions

  • 2008–2014
    • University of Colorado
      Denver, Colorado, United States
  • 1997–2014
    • University of Colorado at Boulder
      • Department of Integrative Physiology
      Boulder, Colorado, United States
    • University of Maryland, College Park
      • Department of Kinesiology
      College Park, MD, United States
  • 2001
    • Louisiana State University Health Sciences Center New Orleans
      • Department of Medicine
      New Orleans, LA, United States
  • 1998
    • Colorado State University
      Fort Collins, Colorado, United States