Impaired Endothelium-dependent Vasodilation in Overweight and Obese Adult Humans is Not Limited to Muscarinic Receptor Agonists

Muscarinic receptor agonists have primarily been used to characterize endothelium-dependent vasodilator dysfunction with overweight/obesity. Reliance on a single class of agonist, however, yields limited, and potentially misleading, information regarding endothelial vasodilator capacity. The aims of this study were to determine 1) whether the overweight/obesity-related reduction in endothelium-dependent vasodilation extends beyond muscarinic receptor agonists and 2) whether the contribution of nitric oxide (NO) to endothelium-dependent vasodilation is reduced in overweight/obese adults. Eighty-six middle-aged and older adults were studied: 42 normal-weight (54 +/- 1 yr, 21 men and 21 women, body mass index = 23.4 +/- 0.3 kg/m(2)) and 44 overweight/obese (54 +/- 1 yr, 28 men and 16 women, body mass index = 30.3 +/- 0.6 kg/m(2)) subjects. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl-l-arginine, methacholine, bradykinin, substance P, isoproterenol, and sodium nitroprusside were measured by strain-gauge plethysmography. FBF responses to each endothelial agonist were significantly blunted in the overweight/obese adults. Total FBF (area under the curve) to acetylcholine (50 +/- 5 vs. 79 +/- 4 ml/100 ml tissue), methacholine (55 +/- 4 vs. 86 +/- 5 ml/100 ml tissue), bradykinin (62 +/- 5 vs. 85 +/- 4 ml/100 ml tissue), substance P (37 +/- 4 vs. 57 +/- 5 ml/100 ml tissue), and isoproterenol (62 +/- 4 vs. 82 +/- 6 ml/100 ml tissue) were 30%-40% lower in the overweight/obese than normal-weight adults. N(G)-monomethyl-l-arginine significantly reduced the FBF response to acetylcholine to the same extent in both groups. There were no differences between the groups in the FBF responses to sodium nitroprusside. These results indicate that agonist-stimulated endothelium-dependent vasodilation is universally impaired with overweight/obesity. Moreover, this impairment appears to be independent of NO

Basal Endothelial Nitric Oxide Release is Preserved in Overweight and Obese Adults

OBJECTIVE: Impaired basal nitric oxide release is associated with a number of cardiovascular disorders including hypertension, arterial spasm, and myocardial infarction. We determined whether basal endothelial nitric oxide release is reduced in otherwise healthy overweight and obese adult humans.RESEARCH METHODS AND PROCEDURES: Seventy sedentary adults were studied: 32 normal weight (BMI/m(2)), 24 overweight (BMI \u3e or = 25 \u3c 30 kg/m(2)), and 14 obese (BMI \u3e or = 30 kg/m(2)). Forearm blood flow (FBF) responses to intra-arterial infusions of N(g)-monomethyl-L-arginine (5 mg/min), a nitric oxide synthase inhibitor, were used as an index of basal nitric oxide release.RESULTS: N(g)-monomethyl-L-arginine elicited significant reductions in FBF in the normal weight (from 4.1 +/- 0.2 to 2.7 +/- 0.2 mL/100 mL tissue/min), overweight (4.1 +/- 0.1 to 2.8 +/- 0.2 mL/100 mL tissue/min), and obese (3.9 +/- 0.3 to 2.7 +/- 0.2 mL/100 mL tissue/min) subjects. Importantly, the magnitude of reduction in FBF (approximately 30%) was similar among the groups.DISCUSSION: These results indicate that the capacity of the endothelium to release nitric oxide under basal conditions is not compromised in overweight and obese adults

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale

Metabolic Syndrome and Endothelial Fibrinolytic Capacity in Obese Adults

The metabolic syndrome (MetS) often accompanies obesity and contributes to the increased risk of atherothrombotic events with increased body fatness. Indeed, the risks for coronary artery disease and acute vascular events are greater with obesity combined with MetS compared with obesity alone. Endothelial release of tissue-type plasminogen activator (t-PA) is a key defense mechanism against thrombosis and has been shown to be impaired with obesity. The aim of the present study was to determine whether the presence of MetS exacerbates endothelial fibrinolytic dysfunction in obese adults. Net endothelial release of t-PA was determined in vivo in response to intrabrachial infusions of bradykinin and sodium nitroprusside in 47 sedentary adults: 15 normal weight (age 57 +/- 2 yr; body mass index 22.9 +/- 0.5 kg/m(2)), 14 obese but otherwise healthy (55 +/- 1 yr; 29.4 +/- 0.3 kg/m(2)), and 18 obese with MetS (55 +/- 2 yr; 32.3 +/- 1 kg/m(2)). MetS was established according to National Cholesterol Education Program ATP III criteria. Net release of t-PA antigen to bradykinin was approximately 50% lower (P \u3c 0.01) in the obese (from 2.5 +/- 1.9 to 37.1 +/- 5.3 ng.100 ml tissue(-1).min(-1)) and obese with MetS (from 0.4 +/- 0.8 to 32.5 +/- 3.8 ng.100 ml tissue(-1).min(-1)) compared with normal-weight (from 0.9 +/- 1.0 to 74.3 +/- 8.1 ng.100 ml tissue(-1).min(-1)) subjects. However, there were no significant differences in the capacity of the endothelium to release t-PA in the obese and obese with MetS adults. These results indicate that the presence of the MetS does not worsen the obesity-related endothelial fibrinolytic dysfunction

Endothelin-1 Vasoconstrictor Tone Increases with Age in Healthy Men But Can be Reduced by Regular Aerobic Exercise

Endothelial release of tissue-type plasminogen activator (t-PA) regulates fibrinolysis and is considered to be a primary endogenous defense mechanism against thrombosis. Adiposity is associated with an increased risk of atherothrombotic events. We determined the influence of overweight and obesity on the capacity of the vascular endothelium to release t-PA and the effects of regular aerobic exercise on endothelial t-PA release in previously sedentary overweight and obese adults. First, we studied 66 sedentary adults: 28 normal-weight (BMI \u3c 25 kg/m2); 22 overweight (BMI \u3e or = 25 and \u3c 30 kg/m2); and 16 obese (BMI \u3e or = 30 kg/m2). Net endothelial t-PA release was determined in vivo in response to intrabrachial infusions of bradykinin (BK) and sodium nitroprusside. Second, we studied 17 overweight and obese adults who completed a 3-mo aerobic exercise intervention. Net release of t-PA in response to BK was approximately 45% lower (P \u3c 0.01) in overweight (from 0.1 +/- 0.4 to 41.7 +/- 4.9 ng x 100 ml tissue(-1) x min(-1)) and obese (-0.1 +/- 0.6 to 47.7 +/- 5.2 ng x 100 ml tissue(-1) x min(-1)) compared with normal-weight (0.1 +/- 0.8 to 77.5 +/- 6.7 ng x 100 ml tissue(-1) x min(-1)) adults. There was no difference in t-PA release between the overweight and obese groups. Exercise training significantly increased t-PA release capacity in overweight and obese adults (from -0.3 +/- 0.5 to 37.1 +/- 4.9 ng x 100 ml tissue(-1) x min(-1) before training vs. 1.0 +/- 0.9 to 65.4 +/- 6.3 ng x 100 ml tissue(-1) x min(-1) after training) to levels comparable with those of their normal-weight peers. These results indicate that overweight and obesity are associated with profound endothelial fibrinolytic dysfunction. Importantly, however, regular aerobic exercise can increase the capacity of the endothelium to release t-PA in this at-risk population

ENDOTHELIAL VASODILATOR FUNCTION IN NORMAL WEIGHT ADULTS WITH METABOLIC SYNDROME

Metabolic Syndrome (MetS) typically presents with obesity; however, obesity is not a requisite characteristic for MetS classification and related vascular risk. We tested the hypothesis that MetS, independent of excess adiposity, is associated with impaired endothelial vasodilator dysfunction. Thirty-two sedentary, middle-aged adults were studied: 11 normal weight (9 M/2 F; BMI 24.0±0.3 kg/m2); 11 normal weight with MetS (9 M/2 F; 24.7±0.3 kg/m2); and 10 obese without MetS (8 M/2 F; 31.4±0.5 kg/m2). MetS was established according to NCEP ATP III criteria. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine and sodium nitroprusside were measured via strain-gauge plethysmography. FBF responses to acetylcholine were ~20% lower (PThe accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Influence of Metabolic Syndrome on Biomarkers of Oxidative Stress and Inflammation in Obese Adults

OBJECTIVE: Both obesity and the metabolic syndrome (MetS) have been independently linked with increased oxidative and inflammatory stress. This study tested the hypothesis that obesity with MetS is associated with greater oxidative and inflammatory burden compared with obesity alone.RESEARCH METHODS AND PROCEDURES: Forty-eight normal-weight and 40 obese (20 without MetS; 20 with MetS) adults were studied. MetS was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria. Plasma concentrations of oxidized low-density lipoprotein, C-reactive protein, tumor necrosis factor-alpha, interleukin (IL)-6, and IL-18 were determined by enzyme immunoassay.RESULTS: Plasma biomarkers of oxidative stress and inflammation were lowest in normal-weight controls. Of note, obese MetS adults demonstrated significantly higher plasma concentrations of oxidized low-density lipoprotein (62.3 +/- 3.2 vs. 54.0 +/- 4.0 U/L; p \u3c 0.05), C-reactive protein (3.0 +/- 0.6 vs. 1.5 +/- 0.3 mg/L; p \u3c 0.01), tumor necrosis factor-alpha (2.1 +/- 0.1 vs. 1.6 +/- 0.1 pg/mL; p \u3c 0.05), IL-6 (2.8 +/- 0.4 vs. 1.4 +/- 0.2 pg/mL; p \u3c 0.01), and IL-18 (253 +/- 16 vs. 199 +/- 16 pg/mL; p \u3c 0.01), compared with obese adults without MetS.DISCUSSION: These results suggest that MetS heightens oxidative stress and inflammatory burden in obese adults. Increased oxidative and inflammatory stress may contribute to the greater risk of coronary heart disease and cerebrovascular disease in obese adults with MetS

Regular Aerobic Exercise, Without Weight Loss, Improves Endothelium-dependent Vasodilation in Overweight and Obese Adults.

Lifestyle modification in the form of weight reduction by caloric restriction alone or in combination with regular aerobic exercise significantly improves endothelium-dependent vasodilation in overweight and obese adults. We determined whether regular aerobic exercise, independent of weight loss, improves endothelium-dependent vasodilation in overweight and obese adults. Twenty overweight and obese adults (age 53 +/- 1 years; BMI: 30.2 +/- 0.8 kg/m(2)) were studied before and after a 3-month aerobic exercise training intervention. Forearm blood flow (FBF) responses were determined (via plethysmography) in response to intra-arterial infusion of acetylcholine and sodium nitroprusside. There were no changes in body mass or composition with the intervention. FBF responses to acetylcholine were approximately 35% higher (P \u3c 0.01) after (4.1 +/- 0.9 to 14.7 +/- 4.3 ml/100 ml tissue/min) compared with before (4.2 +/- 0.8 to 11.0 +/- 3 ml/100 ml tissue/min) exercise training. FBF responses to sodium nitroprusside were unchanged. These results indicate that regular aerobic exercise improves endothelium-dependent vasodilation in overweight and obese adults, independent of changes in body mass or composition