Endothelium-dependent Vasomotor Function Research Articles

Impaired Endothelial Vasomotor Function with Borderline-High Triglycerides

Approximately 1 in 3 adults in the United States have a triglyceride (TG) concentration above 150 mg/dL and 1 in 5 adults have TG levels 200 mg/dL or higher. Moreover, the prevalence of suboptimal TGs (>150 mg/dL) has increased 5-fold in middle-aged and older adults over the last 3 decades. While much attention has focused on the cardiovascular effects of high and very high TG levels, where other lipid and metabolic abnormalities are often present, there are currently little data on the influence of borderline-high TG concentrations on vascular health. This represents a critical void in our understanding of the pathogenesis of cardiovascular disease (CVD) with TGs. Impaired endothelial vasomotor function is a central etiologic feature in the development of CVD and associated thrombotic events. We tested the hypothesis that endothelium-dependent vasomotor function is impaired in adults with borderline-high TG concentrations. Thirty-two sedentary, adults were studied: 15 (7M/8F, age: 56±1 yr; BMI: 26.8±0.6 kg/m2) with normal TG (35-140 mg/dL) and 17 (9M/8F, age: 57±1 yr; BMI: 28.7±0.8 kg/m2) with borderline-high TG (150-199 mg/dL) levels. Forearm blood flow (FBF; plethysmography) was determined in response to the intra-arterial infusion: acetylcholine (ACh) (4.0, 8.0, and 16.0 mg/100 mL tissue/min), sodium nitroprusside (1.0, 2.0, and 4.0 mg/100 mL tissue/min) and selective ETa receptor blocker (BQ-123, 100 nmol/min for 60 min). FBF response to ACh was significantly lower (~20%) in the borderline-high TG (from 4.7±0.3 to 11.6+0.6 mL/100 mL tissue/min) vs normal TG (from 4.3±0.3 to 14.6±0.5 mL/100 mL tissue/min) group. There were no significant group differences in the FBF responses to sodium nitroprusside. BQ-123 elicited a significant vasodilator response (~20%) in the borderline-high TG adults but did not alter FBF in the normal TG adults. Co-infusion of BQ-123 did not affect FBF responses to ACh in normal TG group but resulted in an ~30% increase in Ach-induced vasodilation (from 4.3±0.4 to 15.1±0.7 mL/100 mL tissue/min; P<0.05) in borderline-high TG group. Triglyceride levels were significantly and inversely associated with total FBF response to ACh (r=-0.63) and positively associated with the peak FBF response to BQ-123 (r=0.53; P<0.05). These results indicate that borderline-high TG concentrations are associated with diminished endothelium-dependent vasodilation and enhanced ET-1-mediated vasoconstrictor tone. Impaired endothelial vasomotor function may underlie the increased risk of CVD in adults with borderline-high TG levels. Nothing to disclose This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Long-Term Intracoronary Structural and Vasomotor Assessment of the ABSORB Bioresorbable Vascular Scaffold

We systematically categorized the longer-term (≥3 years) structural and functional characteristics of the ABSORB bioresorbable vascular scaffold (BVS) using optical coherence tomography imaging and coronary vasomotor reactivity testing and further compared the functional characteristics of BVS stented versus remote coronary segments. A total of 92 patients (mean age 56.4 ± 9.7 years, 22.8% women) who underwent percutaneous coronary intervention (76% with acute coronary syndrome) using the ABSORB BVS (112 lesions) were included. Optical coherence tomography analysis (38,790 visible struts) comprised in-segment quantitative lumen/plaque and semiquantitative plaque composition analysis of the neointimal pattern. Epicardial endothelium-dependent and-independent vasomotion was defined as any vasodilatation at low/intermediate intracoronary dose of acetylcholine (ACh) and nitroglycerine, assessed using quantitative coronary angiography. At a median time of 3.2 years follow-up, 79.8% of BVS segments still demonstrated visible struts with a predominant neointimal fibrotic healing pattern in 84% of BVS segments, with 99.5% of struts demonstrating coverage with apposition. Compared with remote segments, BVS segments demonstrated less endothelium-dependent vasodilatation at low (p=0.06) and intermediate ACh doses (p=0.04). Hypertension, longer time interval from index percutaneous coronary intervention, and the degree of in-BVS segment neointimal volume (p <0.03 for all) were each independently associated with abnormal BVS endothelium-dependent vasomotor function. Endothelium-independent function was more likely preserved in non-BVS (remote) segments compared with BVS segments (p=0.06). In conclusion, at 3+ years post-ABSORB BVS insertion, the rate of complete scaffold resorption was low and residual strut presence was high, with a dominant fibrous healing response contributing toward neointimal hyperplasia and endothelium-dependent and-independent vasomotor dysfunction.

Resting and recruitable endothelial function - Evidence of two distinct circadian patterns.

Evidence of a circadian rhythm in endothelium-dependent vasomotor function, with a nadir in Flow-Mediated Dilation (FMD) in the early morning hours, has been previously reported. These changes have been proposed to be one of the mechanisms explaining the circadian pattern in the incidence of cardiovascular events. We set out to investigate the circadian rhythm of FMD, low-flow mediated dilation (L-FMC) and sympathetic vascular tone. 10 young healthy male volunteers (mean age, 28.9±3.7 years) underwent measurements of radial artery endothelium-dependent FMD and L-FMC at 8AM, 2PM and 8PM on the same day. Sympathetic vascular tone was assessed with laser Doppler and Fourier transform analysis. Compared with 2PM and 8PM, FMD decreased markedly in the early morning (2.9±3.4%; 6.2±2.9%; 6.0±4.0%; P = 0.007). In contrast, L-FMC was maximal at 8AM, decreased significantly at 2PM, and returned to higher values at 8PM (-5.1±1.3%; -2.7±2.0%; -4.6±2.2%; P = 0.030), such that the composite endpoint of endothelial function (sum of FMD+L-FMC) was not significantly different among timepoints. Vascular sympathetic tone was maximal early in the morning and lowest in the evening (P = 0.014) without a correlation with the changes in FMD or L-FMC. Endothelial responsiveness (FMD) and basal tone (L-FMC) appear to follow different circadian rhythms, with an impaired responsiveness in the early morning and a nadir in baseline tone in the early afternoon.

Functional vascular contributions to cognitive impairment and dementia: mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging.

Increasing evidence from epidemiological, clinical and experimental studies indicate that age-related cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including Alzheimer's disease. Understanding and targeting the age-related pathophysiological mechanisms that underlie vascular contributions to cognitive impairment and dementia (VCID) are expected to have a major role in preserving brain health in older individuals. Maintenance of cerebral perfusion, protecting the microcirculation from high pressure-induced damage and moment-to-moment adjustment of regional oxygen and nutrient supply to changes in demand are prerequisites for the prevention of cerebral ischemia and neuronal dysfunction. This overview discusses age-related alterations in three main regulatory paradigms involved in the regulation of cerebral blood flow (CBF): cerebral autoregulation/myogenic constriction, endothelium-dependent vasomotor function, and neurovascular coupling responses responsible for functional hyperemia. The pathophysiological consequences of cerebral microvascular dysregulation in aging are explored, including blood-brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages, microvascular rarefaction, and ischemic neuronal dysfunction and damage. Due to the widespread attention that VCID has captured in recent years, the evidence for the causal role of cerebral microvascular dysregulation in cognitive decline is critically examined.

CORRECTION OF VASCULAR DISTURBANCES IN PATIENTS WITH CHRONIC OBSTRUCIVE PULMONARY DISEASE IN COMBINATION WITH THE HYPERTONIC DISEASE: NEW DIRECTIONS OF PATHOGENETIC THERAPY

The purpose of the study was to study of effects of sulodexide on clinical and functional parameters in patients with chronic obstructive pulmonary disease (COPD) in combination with hypertension. 40 COPD patients were examined. Patients were divided into two groups of 20 people. One group received only basic COPD therapy and antihypertensive treatment, the other group - basic and antihypertensive therapy in combination with sulodexide. After a year of observation the assessment of the clinical course of the disease, and ventilatory lung function, cardiopulmonary hemodynamics, endothelium-dependent vasomotor function was done. In patients, additionally treated with sulodexide, the following parameters were marked: stabilization of blood pressure parameters, reduction of dizziness and headaches, increase of tolerance to physical load, reducing the number of exacerbations, improvement in spirometry, lung diffusion capacity, improvement of pulmonary hemodynamics parameters and improvement of endothelium-dependent vasodilation. Thus, the positive effect of sulodexide on clinical and functional parameters indicates the feasibility of further study of the use of angioprotectors in complex pathogenetic therapy of COPD.

Exercise improves endothelial function: A local analysis of production of nitric oxide and reactive oxygen species

This study aimed at investigating the acute effects of aerobic exercise on endothelium-dependent vasomotor function of rat aorta, as well as mechanisms involved in endothelial nitric oxide (NO) bioactivity.Wistar rats were assigned to either a resting control (C, n = 21) or acutely exercised (E, n = 21) groups (60 min, 55–60% of maximum speed). After exercise, thoracic aorta was excised and cut into rings. Two rings were promptly applied to evaluate vasomotor function and the rest of aorta was used for additional measurements.Acute exercise significantly improved maximum ACh-induced relaxation (C, 91.6 ± 1.2 vs. E, 102.4 ± 1.7%, p < 0.001) and sensitivity to ACh (C, −7.3 ± 0.06 vs. E, −7.3 ± 0.02 log M, p < 0.01), and was accompanied by significantly increases on serine1177 eNOS phosphorylation, reflecting its enhanced activation. However, acute exercise also enhanced both superoxide and hydrogen peroxide production, as assayed by dihydroethidium oxidation, lucigenin chemiluminescence and Amplex Red assays. We also provided evidence for Nox2 NADPH oxidase (Nox) activation through gp91dstat-mediated inhibition of superoxide signals. Enhanced arterial relaxations associated with acute exercise were nearly-completely prevented by catalase, suggesting a role for paracrine hydrogen peroxide. Despite increased detectable oxidant generation, cellular oxidative stress was not evident, as suggested by unaltered GSH:GSSG ratio and lipid hydroperoxides.Collectively, these results demonstrate that one bout of moderate aerobic exercise improves endothelial function by increasing NO bioavailability, while superoxide and hydrogen peroxide are generated in a controlled fashion.

Longitudinal evaluation of endothelial function in children and adolescents with type 1 diabetes mellitus: A long‐term follow‐up study

Type 1 diabetes (T1DM) predisposes to cardiovascular disease, increasing the risk to develop atherosclerosis. In the pediatric population, the cardiovascular risk may be evaluated examining endothelial function by a non-invasive ultrasound technique, namely flow-mediated dilation (FMD) of the brachial artery. The aims of this study were the longitudinal evaluation of the potential change in the endothelium-dependent vasomotor function in children and adolescents with T1DM and the identification of clinical and laboratory data correlated to modifications. We studied 39 T1DM patients (20 girls and 19 boys; aged 11.2 ± 3.72 years). FMD and blood samples were obtained from all patients at baseline (time 0) and after a follow up of at least 1 year (time 1). FMD was also evaluated in 45 healthy controls (22 boys, 23 girls) aged 10.2 ± 3.05 years. At time 0, 43.6% of T1DM patients presented an impaired FMD. FMD at time 1 revealed a dramatic impairment of endothelial function: altered FMD values were shown in 61.5% of patients and it got worse in 74.3% of them. Longitudinally, boys had a greater impairment of FMD than girls. At baseline, multivariate analysis identified only sex as significant predictor of FMD (β = 0.470, P = 0.029). Because endothelial dysfunction appears earlier in diabetic children, they are at higher risk to develop atherosclerosis. Our results suggest the usefulness of FMD as a tool to stratify pediatric T1DM patients according to their cardiovascular risk and to follow them up longitudinally.

Exercise training and vascular cell phenotype in a swine model of familial hypercholesterolaemia: conduit arteries and veins

What is the central question of this study? Does endurance exercise training cause anti-atherogenic effects on the endothelium in a swine model of familial hypercholesterolaemia (FH), and how are these effects distributed across veins, arteries and multiple vascular territories within each system? What is the main finding and its importance? Coronary artery endothelium-dependent vasomotor function was depressed in sedentary FH pigs compared with sedentary control animals, and exercise training did not change vasomotor function within FH. In systemic conduit arteries and veins, few effects of FH on endothelial cell protein expression were noted, including both pro- and anti-atherogenic changes. These findings suggest that exercise training does not produce a consistently improved endothelial cell phenotype in either coronary or systemic conduit vessels in this swine model of FH. Exercise training has emerged as an intervention for the primary and secondary prevention of coronary artery disease, but the mechanisms through which training reduces relative risk are not completely understood. The goal of this study was to investigate the impact of endurance exercise training on vasomotor function and vascular cell phenotype in coronary arteries and systemic conduit arteries and veins against a background of advanced atherosclerosis. We tested the hypothesis that exercise training restores endothelial vasomotor function and produces an anti-atherogenic endothelial and smooth muscle cell phenotype in familial hypercholesterolaemic (FH) swine. The study included 30 FH (15 exercised and 15 sedentary) and 13 non-FH control male castrated swine. The exercise-training intervention consisted of treadmill running 5 days per week for 16-20 weeks. Tissues sampled at sacrifice included vascular rings from the coronary circulation for vasomotor function experiments (dose-dependent bradykinin-induced vasorelaxation) and endothelial cells (ECs) from isolated segments of the thoracic aorta, the carotid, brachial, femoral and renal arteries, as well as each corresponding regionally associated vein, and from the abdominal vena cava, the right coronary and internal mammary arteries. Smooth muscle cells were sampled from the right coronary artery only. Vascular cell phenotype was assessed by immunoblotting for a host of both pro- and anti-atherogenic markers [e.g. endothelial nitric oxide synthase, p67phox, superoxide dismutase 1 (SOD1)]. Coronary artery endothelium-dependent vasomotor function was depressed in sedentary FH pigs compared with sedentary control pigs, and exercise training did not change vasomotor function within FH. In contrast, only scattered effects of FH on EC phenotype were noted across the vasculature, which included both pro- and anti-atherogenic changes in EC protein expression (e.g. increased endothelial nitric oxide synthase in carotid artery ECs, decreased p67phox in brachial artery ECs, but decreased expression of the antioxidant protein SOD1 in thoracic vena cava; all P < 0.05). In thoracic vena cava ECs, this deficit was corrected by exercise training, while no other effects of exercise were observed in conduit vessel EC phenotype. Thus, while exercise training abrogated the adverse effect of hypercholesterolaemia on thoracic vena cava SOD1 expression, it appears that exercise training does not produce a consistently improved EC phenotype in either coronary or systemic conduit vessels in this FH swine model.

Monocyte–Platelets Aggregates as Cellular Biomarker of Endothelium-Dependent Coronary Vasomotor Dysfunction in Patients with Coronary Artery Disease

Monocyte-platelet aggregates (MPA) are increased in patients with acute coronary syndrome. We investigated whether MPA are associated with the presence of functionally significant coronary stenoses or with coronary arterial endothelial dysfunction. One hundred forty five patients undergoing elective coronary angiography were prospectively enrolled. Functional significance of coronary stenosis was assessed by fractional flow reserve (FFR). Thirty randomly selected patients underwent pacing protocol to evaluate Coronary endothelium-dependent vasomotor function (CVF). Whole blood was drawn to evaluate MPA. In patients with FFR ≤ 0.8 (FFRpos, n = 75), MPA did not significantly differ from FFR >0.8 patients (FFRneg, n = 70) (38.1% [25.7-56.6] vs. 34.0% [20.5-49.9], p = 0.08). CVF was similar in FFRpos and FFRneg patients (percent vessel diameter change, %VDC = 7.19 % [6.01-10.9] vs. 8.0 % [0.81-9.80], p = 0.78). Yet, patients with abnormal CVF showed higher MPA as compared to patients with preserved CVF (28.3% [28.8-53.4] vs. 20.5 % [17.0-32.9], p = 0.01). Moreover, MPA was inversely correlated with %VDC (R2 = 0.26, p < 0.01). MPA levels are significantly higher in patients with abnormal coronary vasomotor function regardless of the presence of functionally significant coronary stenosis.

Selective Activation of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Mediates C-Reactive Protein–Evoked Endothelial Vasodilator Dysfunction in Coronary Arterioles

Studies in cultured endothelium implicate that lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) or Fcγ receptor II (CD32) contributes to the proatherogenic effects of C-reactive protein (CRP). However, the identity of the receptors linking to deleterious actions of CRP in vasomotor regulation remains unknown. We tested the hypothesis that LOX-1 contributes to adverse effects of CRP on endothelium-dependent vasomotor function in resistance arterioles. Porcine coronary arterioles were isolated for vasoreactivity study, dihydroethidium fluorescence staining of superoxide, immunohistochemical localization of receptors, immunoprecipitation of receptor/CRP interaction, and protein blot. Intraluminal treatment of pressurized arterioles with a pathophysiological level of CRP (7 µg/mL; 60 minutes) attenuated endothelium-dependent nitric oxide-mediated and prostacyclin-mediated dilations to serotonin and arachidonic acid, respectively. LOX-1 and CD32 were detected in the endothelium of arterioles. Blockade of LOX-1 with either pharmacological antagonist κ-carrageenan or anti-LOX-1 antibody prevented the detrimental effect of CRP on vasodilator function, whereas anti-CD32 antibody treatment was ineffective. Denudation of endothelium and blockade of LOX-1 but not CD32 prevented CRP-induced elevation of superoxide in the vessel wall. CRP was coimmunoprecipitated with LOX-1 and CD32 from CRP-treated arterioles. Similarly, LOX-1 and CD32 blockade prevented CRP-induced arteriolar expression of plasminogen activator inhibitor-1, a thrombogenic protein. CRP elicits endothelium-dependent oxidative stress and compromises nitric oxide-mediated and prostacyclin-mediated vasomotor function via LOX-1 activation. In contrast, both LOX-1 and CD32 mediate plasminogen activator inhibitor-1 upregulation in arterioles by CRP. Thus, activation of LOX-1 and CD32 may contribute to vasomotor dysfunction and proatherogenic actions of CRP, respectively.

Darbepoetin enhances endothelium-dependent vasomotor function in patients with stable coronary artery disease only after preceding ischaemia/reperfusion

Vasoprotective effects of erythropoietin in animal models are mediated by endothelium-derived NO and/or mobilization of EPCs (endothelial progenitor cells) and may be enhanced by ischaemia: whether they are present in humans is unknown. We examined whether the erythropoietin analogue darbepoetin improves FMD (flow-mediated dilatation), a measure of endothelium-derived NO, and whether this is influenced by preceding I/R (ischaemia/reperfusion). A total of 36 patients (50-75 years) with stable coronary artery disease were randomized to receive a single dose of darbepoetin (300 μg) or saline placebo. FMD was measured at the brachial artery using high-resolution ultrasound. CD133⁺/CD34⁺/VEGFR2⁺ (vascular endothelial growth factor receptor 2) circulating EPCs were enumerated by flow cytometry. Measurements were made immediately before darbepoetin/placebo and at 24 h, 72 h and 7 days. At 24 h, FMD was repeated after 20 min of I/R of the upper limb. A further group of 11 patients was studied according to the same protocol, all receiving darbepoetin, with omission of forearm I/R at 24 h. Immunoreactive erythropoietin peaked at 24 h and remained elevated at approximately 50-fold of baseline at 72 h. FMD did not differ significantly between groups at 24 h (before I/R). At 72 h (48 h after I/R), FMD was greater (by 2.3±0.5% in the darbepoetin compared with the placebo group, a 66% increase over baseline; P<0.001) and greater than FMD at the same time point without preceding I/R (P<0.01). Increases in CD133⁺/CD34⁺/VEGFR2⁺ cells after darbepoetin did not differ according to the presence or absence of preceding I/R. Preceding I/R is required for darbepoetin to enhance endothelial function, possibly by increasing expression of the erythropoietin receptor and by a mechanism likely to involve Akt/NO rather than circulating EPCs.

Bradykinin does not mediate remote ischaemic preconditioning or ischaemia-reperfusion injury in vivo in man

ObjectiveTo examine whether endogenous bradykinin mediates the endothelium-dependent vasomotor dysfunction induced by ischaemia-reperfusion injury, or the protection afforded by remote ischaemic preconditioning in vivo in man.DesignRandomised double-blind, cross-over study.SettingsRoyal Infirmary...

Changes in the control of skin blood flow with exercise training: where do cutaneous vascular adaptations fit in?

Heat is the most abundant byproduct of cellular metabolism. As such, dynamic exercise in which a significant percentage of muscle mass is engaged generates thermoregulatory demands that are met in part by increases in skin blood flow. Increased skin blood flow during exercise adds to the demands on cardiac output and confers additional circulatory strain beyond that associated with perfusion of active muscle alone. Endurance exercise training results in a number of physiological adaptations which ultimately reduce circulatory strain and shift thermoregulatory control of skin blood flow to higher levels of blood flow for a given core temperature. In addition, exercise training induces peripheral vascular adaptations within the cutaneous microvasculature indicative of enhanced endothelium-dependent vasomotor function. However, it is not currently clear how (or if) these local vascular adaptations contribute to the beneficial changes in thermoregulatory control of skin blood flow following exercise training. The purpose of this Hot Topic Review is to synthesize the literature pertaining to exercise training-mediated changes in cutaneous microvascular reactivity and thermoregulatory control of skin blood flow. In addition, we address mechanisms driving changes in cutaneous microvascular reactivity and thermoregulatory control of skin blood flow, and pose the question: what (if any) is the functional role of increased cutaneous microvascular reactivity following exercise training?

Improvement of Endothelial Function With Dietary Flavanols Is Associated With Mobilization of Circulating Angiogenic Cells in Patients With Coronary Artery Disease

In patients with coronary artery disease (CAD) medically managed according to currently accepted guidelines, we tested whether a 1-month dietary intervention with flavanol-containing cocoa leads to an improvement of endothelial dysfunction and whether this is associated with an enhanced number and function of circulating angiogenic cells (CACs). Dietary flavanols can improve endothelial dysfunction. The CACs, also termed endothelial progenitor cells, are critical for vascular repair and maintenance of endothelial function. In a randomized, controlled, double-masked, cross-over trial, 16 CAD patients (64+/-3 years of age) received a dietary high-flavanol intervention (HiFI [375 mg]) and a macronutrient- and micronutrient-matched low-flavanol intervention (LoFI [9 mg]) twice daily in random order over 30 days. Endothelium-dependent vasomotor function, as measured by flow-mediated vasodilation of the brachial artery, improved by 47% in the HiFI period compared with the LoFI period. After HiFI, the number of CD34+/KDR+-CACs, as measured by flow cytometry, increased 2.2-fold as compared with after LoFI. The CAC functions, as measured by the capacity to survive, differentiate, proliferate, and to migrate were not different between the groups. The HiFI led to a decrease in systolic blood pressure (mean change over LoFI: -4.2+/-2.7 mm Hg), and increase in plasma nitrite level (mean change over LoFI: 74+/-32 nM). Applying a mixed-effects linear regression model, the results demonstrated a significant increase in flow-mediated vasodilation and a decrease in systolic blood pressure with increasing levels of CD34+/KDR+-CACs. Sustained improvements in endothelial dysfunction by regular dietary intake of flavanols are associated with mobilization of functional CACs. (Effect of Cocoa Flavanols on Vascular Function in Optimally Treated Coronary Artery Disease Patients: Interaction Between Endothelial Progenitor Cells, Reactivity of Micro- and Macrocirculation; NCT00553774).

Dietary fat differentially influences regulatory endothelial function during the postprandial state in patients with metabolic syndrome: From the LIPGENE study

Objective To investigate whether endothelium-dependent vasomotor function and plasma levels of cellular adhesion molecules are affected by diets with different fat quantity and quality during the postprandial state in subjects with the metabolic syndrome (MetS). Methods Patients were randomly assigned to one of four isoenergetic diets distinct in fat quantity and quality: high-SFA (HSFA); high-MUFA (HMUFA) and two low-fat, high-complex carbohydrate (LFHCC) diets, supplemented with 1.24 g/day of long chain n-3 PUFA (LC n-3 PUFA) or placebo for 12 weeks each. Flow-associated vasodilatation of the brachial artery and postprandial plasma levels of total nitrites, nitric oxide (NO) synthase, soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and P-selectin were assessed post-intervention. Results Post-intervention postprandial flow-associated vasodilatation was significantly higher after the HMUFA diet ( P < 0.05) compared to subjects adhering to the other three diets. Consistently, the postprandial NO synthase response significantly increased during the HMUFA compared with the HSFA and LFHCC (placebo) diets. Postprandial sICAM-1 levels were lower during the HMUFA than during the HSFA and LFHCC n-3 diets. Conclusions Our data support the notion that the HMUFA diet improves postprandial endothelial cell function and decreases postprandial plasma sICAM-1 concentrations in patients with the MetS. These findings suggest that the postprandial state is important for understanding possible cardio-protective effects associated with the Mediterranean diet particularly in subject with the MetS.

Cyclooxygenase and thromboxane/prostaglandin receptor contribute to aortic endothelium-dependent dysfunction in aging female spontaneously hypertensive rats

Cyclooxygenase (COX)-derived vasoconstrictory prostanoids contribute to impaired endothelium-dependent vasorelaxation in aging male (m) spontaneously hypertensive rats (SHR); however, vasomotor responses in aging female (f) SHR and sex differences in aging SHR are unknown. Examining mechanisms governing dysfunction in aging fSHR will contribute to understanding sex-dependent vascular complications in advanced hypertension. Aortic endothelium-dependent relaxation dose responses (ACh) of 16- and 30-wk-old mSHR and fSHR and normotensive Wistar-Kyoto rats were examined in the absence (no drug control) and presence of COX inhibition [indomethacin (Indo)] and thromboxane/prostaglandin receptor inhibition (SQ-29548). No drug control-treated 16-wk mSHR exhibited considerable blunting of the peak relaxation response to ACh (e.g., 77 +/- 4% relaxation to 10(-5) mol/l) vs. Wistar-Kyoto controls (89 +/- 6%), and greater dysfunction occurred in 30-wk mSHR (63 +/- 2%). Interestingly, ACh relaxations of fSHR were unimpaired at 16 wk (101 +/- 2% to 10(-5) mol/l), but blunted in 30 wk (76 +/- 4%). Indo and SQ-29548 restored robust ACh vasorelaxation in all groups (e.g., 113 +/- 3 and 112 +/- 3%, respectively, in Indo- and SQ-29548-treated 30-wk fSHR). Aortic COX-1 protein expression was elevated by 75% in 30-wk vs. 16-wk fSHR, whereas group-averaged ACh-stimulated aortic PGI(2) release (assessed as 6- keto-PGF(1alpha)) was 30% greater in 30-wk vs. 16-wk fSHR (9,926 +/- 890 vs. 7,621 +/- 690 pg.ml(-1).mg dry wt(-1)), although this did not reach significance (P = 0.0758). Dramatic deterioration of endothelium-dependent vasomotor function in fSHR across this age range involves COX and thromboxane/prostaglandin receptor, supporting a mechanism of impairment similar to that which occurs in aging mSHR.

Time‐dependency of angiotensin II mediated vasomotor dysfunction

Angiotensin II (AngII), the main effector of the renin‐angiotensin system, plays an essential role in the regulation of blood pressure and it has been implicated in the pathogenesis of cardiovascular diseases. While AngII is known to alter endothelial function, the time‐course of this response remains poorly understood. The aim of this study was to compare the effects of acute vs chronic angiotensin II treatment on endothelium‐dependent vasomotor function. Wire myography was used to assess vasomotor function of aortic rings obtained from C57BL/6J male mice. Aortic rings were incubated with angiotensin II for either either 15 minutes or 4 hours. In another group, aortic rings were isolated from WT mice subjected to chronic AngII infusion (Alzet pump) at a rate of 2000 ng/kg/min for 14 days. Endothelium‐dependent vasomotor function was assessed by monitoring acetylcholine‐induced vasorelaxation. While AngII exposure for 15 min did not alter endothelium‐dependent vasomotor function, 4 h incubation with AngII significantly (~50%) impaired endothelium dependent vasodilation, compared to untreated rings. A similar level of vasomotor impairment was noted in aortic rings from mice subjected to chronic AngII infusion. These findings reveal a time‐dependency of AngII mediated vasomotor dysfunction and indicates that this response occurs via a mechanism that likely involves new protein synthesis. (HL26441)

P53 Impairs Endothelium-Dependent Vasomotor Function Through Transcriptional Upregulation of P66shc

The transcription factor, p53, and the adaptor protein, p66shc, both play essential roles in promoting oxidative stress in the vascular system. However, the relationship between the two in the context of endothelium-dependent vascular tone is unknown. Here, we report a novel, evolutionarily conserved, p53-mediated transcriptional mechanism that regulates p66shc expression and identify p53 as an important determinant of endothelium-dependent vasomotor function. We provide evidence of a p53 response element in the promoter of p66shc and show that angiotensin II-induced upregulation of p66shc in endothelial cells is dependent on p53. In addition, we demonstrate that downregulation of p66shc expression, as well as inhibition of p53 function in mice, mitigates angiotensin II-induced impairment of endothelium-dependent vasorelaxation, decrease in bioavailable nitric oxide, and hypertension. These findings reveal a novel p53-dependent transcriptional mechanism for the regulation of p66shc expression that is operative in the vascular endothelium and suggest that this mechanism is important in impairing endothelium-dependent vascular relaxation.

Abstract 2567: Late Catch-Up Recovery from Endothelial Vasomotor Dysfunction in Infarct-Related Coronary Artery Treated with Sirolimus-Eluting Stent in Patients with Acute Myocardial Infarction

Myocardial ischemia-reperfusion causes endothelial injury in the infarct-related coronary artery. We have previously shown that sirolimus-eluting stent (SES) implantation can aggravate endothelium-dependent vasomotor dysfunction in infarct-related coronary arteries. This study examined effects of SES implantation on duration of reperfusion-induced endothelial dysfunction in infarct-related coronary arteries. This study enrolled 44 patients with a first acute myocardial infarction (AMI) due to occlusion of the left anterior descending coronary artery (LAD) and successful reperfusion therapy using SESs (n = 22) or bare metal stents (BMS, n = 22). Vasomotor function of LAD in response to acetylcholine (ACh) was repeated 2 weeks, 6 months, and 9 months after AMI. Patients with either residual stenosis or in-stent restenosis in LAD were not included in this study. The vasomotor function was also assessed in 20 control subjects for comparison with that in AMI patients. The SES and BMS groups were similar in terms of AMI-related variables including peak CK levels and 2 week LVEF. At 2 weeks after AMI, SES-treated LAD had greater impairment of epicardial dilation and less blood flow increase in response to ACh than BMS-treated LAD (diameter response; 12% vs. 34% of controls, blood flow response; 23% vs. 76% of controls, at 10 μg/min of ACh, respectively). In BMS-treated LAD, the responses of epicardial diameter and blood flow to ACh had recovered to levels similar to those of controls at 6 months (diameter response; 94% of controls, blood flow response; 92% of controls), and the responses showed no further improvement from 6 to 9 months. In SES-treated LAD, the responses were improved but remained lowered compared with BMS-treated LAD at 6 months (diameter response; 58% of controls, blood flow response; 74% of controls). However, the responses in SES-treated LAD at 9 months showed further improvement to levels near to those of BMS-treated LAD or controls (diameter response; 79% of controls, blood flow response; 88% of controls). Although incomplete, the adverse effects of SES on endothelium-dependent vasomotor function in infarct-related coronary arteries were restored through late catch-up recovery after stent implantation.

Impact of a Long-Term Sildenafil Treatment on Pressor Response in Conscious Rats With Insulin Resistance and Hypertriglyceridemia

Insulin resistance constitutes a risk factor for endothelial dysfunction and subsequent cardiovascular diseases including hypertension. Daily treatment with phosphodiesterase type 5 (PDE5) inhibitors has beneficial effects on endothelial function in men with increased cardiovascular risk. Endothelium-dependent vasomotor function is ultimately linked to blood pressure (BP) regulation. We postulated that sildenafil would ameliorate BP and biological markers of endothelial function in fructose-fed rats (FFRs). Wistar rats were fed a standard chow or a 60% fructose-enriched diet containing 12% fat for 8 weeks (FFR). From week 6 through 8, sildenafil (twice a day subcutaneously, 20 mg/kg) was administered followed by a 1-week washout period. At the end of the washout period, BP was recorded using radiotelemetry following cumulative infusion of norepinephrine (from 50 to 400 ng/kg/min). FFR displayed both an impaired glucose tolerance and elevated triglyceridemia. The latter was corrected by sildenafil treatment. Resting BP was similar in all rats, whereas pressor responses were significantly enhanced in FFR (maximal increase in mean BP to norepinephrine: 25.6 +/- 3.8 vs. 40.8 +/- 4.0 mm Hg, P < 0.05) and normalized by sildenafil treatment (24.9 +/- 5.3 mm Hg, not significant vs. control). Urinary levels of 8-isoprostanes and thromboxane B(2) were increased in FFR and corrected by sildenafil treatment. Thus, chronic treatment with sildenafil normalized BP regulation in an experimental model of insulin resistance and hypertriglyceridemia while restoring normal excretion of urinary biological markers of oxidative stress and cyclooxygenase-derived vasoconstrictors. The modulation of ROS and cyclooxygenase-derived vasoconstrictors generation by a chronic treatment with sildenafil may represent an added benefit beyond PDE5 inhibition.