Circadian Variation in Vascular Function and Regenerative Capacity in Healthy Humans

Background: Bone marrow-derived progenitor cells (PCs) are involved in vascular regeneration and correlate with vascular function and cumulative cardiovascular risk. Systemic inflammation is associated with increased mobilization and differentiation of circulating PCs (CPCs) which may ultimately lead to exhaustion of vascular regenerative capacity. Individuals with coronary artery disease (CAD) exhibit a pro-inflammatory response to a mental stress challenge that has been associated with an elevated risk of adverse outcomes. We sought to determine whether subjects with reduced numbers of circulating PCs (CPCs) are at higher risk of a pro-inflammatory response to acute mental stress. Methods: 500 outpatients with stable CAD were enrolled into the Mental Stress Ischemia Prognosis study and underwent a laboratory-based mental stress protocol. Mononuclear cells expressing CD45med, CD34 and CXCR4 epitopes, known to be enriched for hematopoietic PCs, were enumerated using flow cytometry. Interleukin-6 (IL6) and C-Reactive Protein (CRP) levels were measured before and after mental stress. Baseline and changes in IL6 levels were compared across CPC tertiles using linear regression after adjusting for patient characteristics. Results: Mean age was 63± 9 years, 77% male, 70% white. Median CD34+ CPC count was 1.64 (1.02-2.43 cells/μL. CPC levels were not associated with either the baseline IL6 level (Beta= 0.071 95%CI, -0.091, 0.23) or CRP levels (Beta, 0.60, 95%CI, -0.25, 0.44). However, independent of demographics, CAD risk factors and baseline IL6 levels, lower CD34+/CXCR4+ CPC counts were associated with a higher inflammatory response during mental stress, measured as a rise in IL6 level (Beta= -0.11, 95%CI, -0.20, -0.028). Conclusions: Patients with reduced CPC levels have a greater pro-inflammatory response to mental stress. Thus, the observed higher risk in subjects with impaired regenerative capacity might be at least partly due to a higher stress-related pro-inflammatory response.

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Acute hypoxaemia and vascular function in healthy humans

Experimental Physiology ◽

10.1113/ep086532 ◽

2017 ◽

Vol 102 (12) ◽

pp. 1635-1646 ◽

Cited By ~ 9

Author(s):

N. C. S. Lewis ◽

A. R. Bain ◽

K. W. Wildfong ◽

D. J. Green ◽

P. N. Ainslie

Keyword(s):

Vascular Function ◽

Healthy Humans

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Assessing the respective contributions of dietary flavanol monomers and procyanidins in mediating cardiovascular effects in humans: randomized, controlled, double-masked intervention trial

American Journal of Clinical Nutrition ◽

10.1093/ajcn/nqy229 ◽

2018 ◽

Vol 108 (6) ◽

pp. 1229-1237 ◽

Cited By ~ 12

Author(s):

Ana Rodriguez-Mateos ◽

Timon Weber ◽

Simon S Skene ◽

Javier I Ottaviani ◽

Alan Crozier ◽

...

Keyword(s):

Total Cholesterol ◽

Vascular Function ◽

Dietary Intervention ◽

Daily Intake ◽

Circulatory System ◽

Cardiovascular Effects ◽

Intervention Trial ◽

Randomized Controlled ◽

Healthy Humans ◽

Relative Contribution

ABSTRACT Background Flavanols are an important class of food bioactives that can improve vascular function even in healthy subjects. Cocoa flavanols (CFs) are composed principally of the monomer (−)-epicatechin (∼20%), with a degree of polymerisation (DP) of 1 (DP1), and oligomeric procyanidins (∼80%, DP2–10). Objective Our objective was to investigate the relative contribution of procyanidins and (−)-epicatechin to CF intake–related improvements in vascular function in healthy volunteers. Design In a randomized, controlled, double-masked, parallel-group dietary intervention trial, 45 healthy men (aged 18–35 y) consumed the following once daily for 1 mo: 1) a DP1–10 cocoa extract containing 130 mg (−)-epicatechin and 560 mg procyanidins, 2) a DP2–10 cocoa extract containing 20 mg (−)-epicatechin and 540 mg procyanidins, or 3) a control capsule, which was flavanol-free but had identical micro- and macronutrient composition. Results Consumption of DP1–10, but not of either DP2–10 or the control capsule, significantly increased flow-mediated vasodilation (primary endpoint) and the concentration of structurally related (−)-epicatechin metabolites (SREMs) in the circulatory system while decreasing pulse wave velocity and blood pressure. Total cholesterol significantly decreased after daily intake of both DP1–10 and DP2–10 as compared with the control. Conclusions CF-related improvements in vascular function are predominantly related to the intake of flavanol monomers and circulating SREMs in healthy humans but not to the more abundant procyanidins and gut microbiome–derived CF catabolites. Reduction in total cholesterol was linked to consumption of procyanidins but not necessarily to that of (−)-epicatechin. This trial was registered at clinicaltrials.gov as NCT02728466.

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Acute hot water immersion is protective against impaired vascular function following forearm ischemia-reperfusion in young healthy humans

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00301.2016 ◽

2016 ◽

Vol 311 (6) ◽

pp. R1060-R1067 ◽

Cited By ~ 20

Author(s):

Vienna E. Brunt ◽

Andrew T. Jeckell ◽

Brett R. Ely ◽

Matthew J. Howard ◽

Dick H. J. Thijssen ◽

...

Keyword(s):

Brachial Artery ◽

Vascular Function ◽

Ischemia Reperfusion ◽

Water Immersion ◽

Reactive Hyperemia ◽

Random Order ◽

Hot Water ◽

Healthy Humans ◽

Time Control ◽

Hot Water Immersion

Ischemia-reperfusion (I/R) injury is a primary cause of poor outcomes following ischemic cardiovascular events. We tested whether acute hot water immersion protects against forearm vascular I/R. Ten (5 male, 5 female) young (23 ± 2 yr), healthy subjects participated in two trials in random order 7–21 days apart, involving: 1) 60 min of seated rest (control), or 2) 60 min of immersion in 40.5°C water (peak rectal temperature: 38.9 ± 0.2°C). I/R was achieved 70 min following each intervention by inflating an upper arm cuff to 250 mmHg for 20 min followed by 20 min of reperfusion. Brachial artery flow-mediated dilation (FMD) and forearm postocclusive reactive hyperemia (RH) were measured as markers of macrovascular and microvascular function at three time points: 1) preintervention, 2) 60 min postintervention, and 3) post-I/R. Neither time control nor hot water immersion alone affected FMD (both, P > 0.99). I/R reduced FMD from 7.4 ± 0.7 to 5.4 ± 0.6% ( P = 0.03), and this reduction was prevented following hot water immersion (7.0 ± 0.7 to 7.7 ± 1.0%; P > 0.99). I/R also impaired RH (peak vascular conductance: 2.6 ± 0.5 to 2.0 ± 0.4 ml·min−1·mmHg−1, P = 0.003), resulting in a reduced shear stimulus (SRAUC·10−3: 22.5 ± 2.4 to 16.9 ± 2.4, P = 0.04). The post-I/R reduction in peak RH was prevented by hot water immersion (2.5 ± 0.4 to 2.3 ± 0.4 ml·min−1·mmHg−1; P = 0.33). We observed a decline in brachial artery dilator function post-I/R, which may be (partly) related to damage incurred downstream in the microvasculature, as indicated by impaired RH and shear stimulus. Hot water immersion was protective against reductions in FMD and RH post-I/R, suggesting heat stress induces vascular changes consistent with reducing I/R injury following ischemic events.

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Abstract 11694: The Gut Hormone Obestatin Induces Nitric Oxide-Dependent Vasodilation and Inhibits Endothelin-1 Activity in Obese Patients

Circulation ◽

10.1161/circ.130.suppl_2.11694 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Francesca Schinzari ◽

Manfredi Tesauro ◽

Angelo Adamo ◽

Alessandra Paolucci ◽

Valentina Rovella ◽

...

Keyword(s):

Nitric Oxide ◽

Vascular Function ◽

Central Obesity ◽

Vascular Dysfunction ◽

Experimental Models ◽

Obese Patients ◽

Healthy Humans ◽

Obesity And Diabetes ◽

Gut Hormone ◽

No Signaling

Obese patients have vascular dysfunction related to impaired nitric oxide (NO)-dependent vasodilation and increased endothelin (ET)-1 activity. Obestatin is a gastrointestinal peptide with favorable metabolic actions linked to obesity and diabetes; it has also been shown to exert cardiovascular benefits in experimental models by producing vascular relaxation via specific activation of endothelium-dependent NO signaling. Here we tested the hypothesis that obestatin might have advantageous impacts on the NO pathway and the ET-1 system in patients with central obesity. To this purpose, forearm blood flow responses to intra-arterial infusion of graded doses of exogenous obestatin (0.2; 0.4; 0.8; 1,6; 3.2 nmol/min, each dose given for 5 min) were assessed in lean subjects (n=5) and in patients with central obesity (n=14), during the concurrent infusion of saline and after NO inhibition by L-NMMA (4 μmol/min for 15 min). In another group of obese patients (n=10), vascular responses to selective blockade of ET A receptors (BQ-123, 10 nmol/min for 60 min) were measured in the absence and the presence of obestatin (0.8 nmol/min). In lean subjects, before NO synthase inhibition obestatin resulted in a progressive increase in forearm flow (60% at the highest dose; P<0.001 vs. baseline); obestatin-induced vasodilation, however, was completely abolished by L-NMMA (P<0.001 vs. saline). Similarly, in obese patients obestatin induced a significant vasodilation (45%; P<0.001 vs. baseline), which was blunted by L-NMMA (16%; P<0.01 vs. saline). Before obestatin, in obese patients ET A receptor blockade resulted in a marked vasodilation (39% flow increase at 60 min; P<0.001 vs. baseline), which was totally abrogated in the presence of obestatin (P<0.001 vs. absence). In conclusion, obestatin produces vasorelaxation in healthy humans via specific activation of endothelium-dependent NO signaling. This beneficial effect of obestatin is preserved in obese arteries, where it is associated with inhibition of ET-1 signaling. These actions of obestatin, therefore, may be important in the normal regulation of vascular function and are clearly relevant to obesity, a condition characterized by increased prevalence of hypertension and cardiovascular complications.

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Forearm vascular control during acute hyperglycemia in healthy humans

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00348.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. E472-E480 ◽

Cited By ~ 22

Author(s):

Ann S. Reed ◽

Nisha Charkoudian ◽

Adrian Vella ◽

Pankaj Shah ◽

Robert A. Rizza ◽

...

Keyword(s):

Vascular Function ◽

Glucose Infusion ◽

Vascular Control ◽

Healthy Human ◽

Healthy Humans ◽

Chronic Hyperglycemia ◽

Human Forearm ◽

Patients With Diabetes ◽

Mild Hyperglycemia ◽

A Site

The vascular endothelium is a site of pathological changes in patients with diabetes mellitus that may be related to severe chronic hyperglycemia. However, it is unclear whether transient hyperglycemia alters vascular function in an otherwise healthy human forearm. To test the hypothesis that acute, moderate hyperglycemia impairs endothelium-dependent forearm vasodilation, we measured vasodilator responses in 25 healthy volunteers (11 F, 14 M) assigned to one of three protocols. In protocol 1, glucose was varied to mimic a postprandial pattern (i.e., peak glucose ∼11.1 mmol/l) commonly observed in individuals with impaired glucose tolerance. Protocol 2 involved 6 h of mild hyperglycemia (∼7 mmol/l). Protocol 3 involved 6 h of euglycemia. Glucose concentration was maintained with a variable systemic glucose infusion. Insulin concentrations were maintained at ∼65 pmol/l by means of a somatostatin and “basal” insulin infusion. Glucagon and growth hormone were replaced at basal concentrations. Forearm blood flow (FBF) was calculated from Doppler ultrasound measurements at the brachial artery. In each protocol, FBF dose responses to intrabrachial acetylcholine (ACh) and sodium nitroprusside (NTP) were assessed at baseline and at 60, 180, and 360 min of glucose infusion. Peak endothelium-dependent vasodilator responses to ACh were not diminished by hyperglycemia in any trial. For example, peak responses to ACh during protocol 2 were 307 ± 47 ml/min at euglycemic baseline and 325 ± 52, 353 ± 65, and 370 ± 70 ml/min during three subsequent hyperglycemic trials ( P = 0.46). Peak endothelium-independent responses to NTP infusion were also unaffected. We conclude that acute, moderate hyperglycemia does not cause short-term impairment of endothelial function in the healthy human forearm.

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Vascular function and endothelin-1: tipping the balance between vasodilation and vasoconstriction

Journal of Applied Physiology ◽

10.1152/japplphysiol.00772.2016 ◽

2017 ◽

Vol 122 (2) ◽

pp. 354-360 ◽

Cited By ~ 21

Author(s):

Steven K. Nishiyama ◽

Jia Zhao ◽

D. Walter Wray ◽

Russell S. Richardson

Keyword(s):

Vascular Function ◽

Vascular Endothelial Cells ◽

Reactive Hyperemia ◽

Flow Mediated Dilation ◽

Vascular Endothelial ◽

Endothelin 1 ◽

Healthy Humans ◽

Blood Flow Control ◽

Potent Vasoconstrictor ◽

The Impact

Endothelin-1 (ET-1), a potent vasoconstrictor secreted by vascular endothelial cells, has been implicated in the pathophysiology of numerous cardiovascular diseases, yet the direct impact of ET-1 on vascular function remains unclear. Therefore, in seven young (23 ± 1 yr) healthy subjects, we investigated the effect of an intra-arterial infusion of ET-1 on reactive hyperemia (RH) and flow-mediated dilation (FMD) in the popliteal artery following 5 min of suprasystolic cuff occlusion. ET-1 infusion significantly attenuated basal leg blood flow (control: 62 ± 4 ml/min, ET-1: 47 ± 9 ml/min), RH [area-under-curve (AUC); control: 162 ± 15 ml, ET-1: 104 ± 16 ml], and peak RH (control: 572 ± 51 ml/min, ET-1: 412 ± 32 ml/min) ( P < 0.05). Administration of ET-1 also reduced FMD (control: 2.4 ± 0.3%, ET-1: 0.5 ± 0.5%) and FMD normalized for shear rate (control: 10.5 × 10−4 ± 2.0 × 10−4%/s−1, ET-1: 0.9 × 10−4 ± 2.8 ×10−4%/s−1). These findings reveal that elevated levels of ET-1 have a significant impact on vascular function, indicating that studies employing RH and FMD as markers of microvascular function and nitric oxide bioavailability, respectively, should exercise caution, as ET-1 can impact these assessments by tipping the balance between vasodilation and vasoconstriction, in favor of the latter. NEW & NOTEWORTHY Endothelin-1 (ET-1) is recognized as the body’s most potent endogenous vasoconstrictor, but the impact of this peptide on vascular function is not well understood. The present study revealed that the intra-arterial administration of ET-1 impaired both microvascular and conduit vessel function of the leg in young, healthy, humans. Studies employing vascular testing in patient cohorts that experience a disease-related increase in ET-1 should thus exercise caution, as ET-1 clearly impairs vascular function.

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Cyclooxygenase inhibition abolishes age-related differences in cerebral vasodilator responses to hypercapnia

Journal of Applied Physiology ◽

10.1152/japplphysiol.01270.2011 ◽

2012 ◽

Vol 112 (11) ◽

pp. 1884-1890 ◽

Cited By ~ 33

Author(s):

Jill N. Barnes ◽

John E. Schmidt ◽

Wayne T. Nicholson ◽

Michael J. Joyner

Keyword(s):

Blood Flow ◽

Vascular Function ◽

Cerebral Blood Flow Velocity ◽

Cerebrovascular Reactivity ◽

Cyclooxygenase Inhibition ◽

Healthy Humans ◽

Age Related ◽

Before And After ◽

End Tidal ◽

Cerebral Vasodilator

Blood flow and vasodilatory responses are altered by age in a number of vascular beds, including the cerebral circulation. To test the role of prostaglandins as regulators of cerebral vascular function, we examined cerebral vasodilator responses to CO2 (cerebrovascular reactivity) in young (26 ± 5 yr; 6 males/6 females) and older (65 ± 6 yr, 5 males/5 females) healthy humans before and after cyclooxygenase inhibition (using indomethacin). Middle cerebral artery velocity (MCAv) responses to stepped hypercapnia were measured before and 90 min after indomethacin. Changes in MCAv during the recovery from hypercapnia (vasoconstrictor responses) were also evaluated before and after indomethacin. Cerebrovascular reactivity was calculated using linear regression between MCAv and end-tidal CO2. Young adults demonstrated greater MCAv (55 ± 6 vs. 39 ± 5 cm/s: P < 0.05) and MCAv reactivity (1.67 ± 0.20 vs. 1.09 ± 0.19 cm·s−1·mmHg−1; P < 0.05) to hypercapnia compared with older adults ( P < 0.05). In both groups MCAv and MCAv reactivity decreased between control and indomethacin. Furthermore, the age-related differences in these cerebrovascular variables were abolished by indomethacin. During the recovery from hypercapnia, there were no age-related differences in MCAv reactivity; however, indomethacin significantly reduced the MCAv reactivity in both groups. Taken together, these results suggest that cerebral blood flow velocity and cerebrovascular reactivity are attenuated in aging humans, and may be due to a loss of prostaglandin-mediated vasodilation.

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Black Soybean Improves Vascular Function and Blood Pressure: A Randomized, Placebo Controlled, Crossover Trial in Humans

Nutrients ◽

10.3390/nu12092755 ◽

2020 ◽

Vol 12 (9) ◽

pp. 2755

Author(s):

Yoko Yamashita ◽

Asuka Nakamura ◽

Fumio Nanba ◽

Shizuka Saito ◽

Toshiya Toda ◽

...

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Blood Pressure ◽

Antioxidant Activity ◽

Vascular Function ◽

Crossover Trial ◽

Black Soybean ◽

Dietary Polyphenols ◽

Healthy Humans ◽

Nitric Oxide Level

Vascular dysfunction and injurious stimuli such as oxidative stress are closely related to the risk of cardiovascular diseases (CVD). Dietary polyphenols are reported to exert beneficial effects in reducing the risk of CVD. Black soybean has been used as a nutritionally rich food and contains abundant polyphenols in its seed coat and grain. Black soybean has many beneficial physiological activities, and its prevention effects on CVD risk were reported mainly in animal experiments. In this study, we performed a randomized, single blind, placebo controlled, crossover trial to investigate the effect of black soybean consumption on the vascular function in healthy humans. Twenty-two healthy adults aged from 30 to 60 completed the four week trial with daily consumption of about a 40 g test material cookie containing 20 g roasted black soybean powder. Body composition, vascular function, biomarkers for oxidative stress, and polyphenol contents in the urine and the plasma were measured. After ingestion of the black soybean cookie, vascular function, which was evaluated by plethysmogram using a Pulse Analyzer®, was improved and systolic blood pressure was decreased. Moreover, nitric oxide levels in plasma and urine were increased, while an oxidative stress biomarker, 8-hydroxy-2′-deoxyguanosine level, in the plasma was decreased accompanied by an increase in the concentration of polyphenols derived from black soybean in plasma and urine. These results suggest that the antioxidant activity of black soybean polyphenols and an increase in the nitric oxide level may contribute to the improvement of vascular function. Thus, black soybean is an attractive food material for improvement of vascular function through decreasing oxidative stress by its potent antioxidant activity and increasing the nitric oxide level in healthy humans.

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- Assessment of Polyphenol-Rich Foods and Beverages on Endothelial (Vascular) Function in Healthy Humans

Innovation in Healthy and Functional Foods ◽

10.1201/b13022-29 ◽

2016 ◽

pp. 454-473 ◽

Cited By ~ 4

Keyword(s):

Vascular Function ◽

Healthy Humans

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