Endothelial Vasodilator Function Research Articles

Improving Cerebrovascular Reactivity After Carotid Endarterectomy Is Not Accompanied by Improvement in Endothelial Vasodilator Function (P10-5.024)

Improving Cerebrovascular Reactivity After Carotid Endarterectomy Is Not Accompanied by Improvement in Endothelial Vasodilator Function (P10-5.024)

Abstract P197: Dietary Quality Determined by Healthy Eating Index-2015 and Endothelial Function in Healthy Adults

The Healthy Eating Index (HEI) is a measure of diet quality based on Dietary Guidelines for Americans and developed in collaboration with the US Department of Health and Human Services and the US Department of Agriculture. Clinical interest in HEI has increased due to its association with obesity, inflammatory biomarkers and risk of coronary heart disease and stroke. Indeed, higher HEI-2015 score has been linked with reduced cardiovascular risk, morbidity, and mortality. Endothelial dysfunction, particularly impaired endothelium-dependent vasodilation, is a central etiological factor underlying cardiovascular risk and events. We and others have previously demonstrated that diets high in saturated fat and other proatherogenic diets are associated with endothelial vasodilator dysfunction. It is currently unknown whether HEI-2015 dietary score is associated with endothelial function. If so, assessing dietary quality based on HEI-2015 may provide targeted nutritional guidance for enhancing vascular health and mitigating cardiovascular risk. The aim of this study was to determine whether HEI-2015 score is associated with endothelial vasodilator function in healthy adults. Using data from 4-day dietary records, HEI-2015 scores were determined in 103 adults (65 M/38 F; age 44-68 years) free of overt cardiometabolic disease. The HEI-2015 score is based on 13 components summed to yield a total score from 0 to 100; higher score representing higher diet quality. The adults were stratified by HEI-2015 score quartiles: Q1: HEI < 52.5 (n=25; 23 M/2 F); Q2: HEI 52.6-59.1 (n=26; 14 M/12 F); Q3: HEI 59.2-66.0 (n=26; 15 M/11 F); and Q4: HEI > 66.0 (n=26; 13 M/13 F). Endothelium-dependent vasodilation was determined by forearm blood flow (FBF) (via plethysmography) responses to intra-arterial infusion of acetylcholine (ACh: 4.0, 8.0, and 16.0 μg/100 mL tissue/min) and sodium nitroprusside (NTP: 1.0, 2.0, and 4.0 μg/100 mL tissue/min). There were no significant differences in endothelium-dependent vasodilation across the HEI-2015 score quartiles. FBF blood responses to ACh were remarkably similar between Q1 (5.1±0.2 to 13.0±0.7 mL/100 mL tissue/min), Q2 (4.3±0.2 to 12.1±0.7 mL/100 mL tissue/min), Q3 (4.4±0.2 to 13.0±0.7 mL/100 mL tissue/min) and Q4 (4.5±0.2 to 14.4±0.6 mL/100 mL tissue/min). Moreover, HEI scores were not significantly associated with the vasodilator response to either ACh (r=0.15, P=0.13) or NTP (r=-0.04; P=0.72). In summary, although diet quality determined by HEI-2015 score has been shown to be associated with increased risk of cardiovascular disease and events, HEI-2015 was not associated endothelial function in mid-life and older adults. Given the established experimental and pathophysiological evidence linking between diet, endothelial vasodilator function and cardiovascular risk, HEI-2015 score is not a sensitive dietary indicator/biomarker of vascular function.

Endothelial and exercise vasodilation are reduced in postmenopausal females with obesity versus lean and overweight.

Obesity (OB) is highly prevalent in females after menopause, especially visceral adipose tissue (VAT) accumulation which contributes to endothelial dysfunction. The endothelium assists in regulating blood flow (BF) during exercise and is attenuated in females with OB. The purpose of this study was to examine upper and lower limb flow-mediated dilation (FMD) and BF regulation during graded low-intensity submaximal exercises in postmenopausal females with BMI in the lean (LN), overweight (OW) and OB categories. Participants were grouped by body mass index (BMI) into LN (BMI 18.5-24.9 kg/m2; n = 11), OW (BMI 25.0-29.9 kg/m2; n = 15), and OB (BMI 30.0-39.9 kg/m2; n = 13). FMD of the brachial (BA-FMD) and superficial femoral arteries (FA-FMD) were assessed. Subsequently, BF and vascular conductance (VC) in the upper (BA-BF and BA-VC) and lower limbs (FA-BF and FA-VC) were measured during separate 3-stage incremental rhythmic handgrip and plantarflexion exercises. Significantly lower FA-FMD (P < 0.05) were seen in OB than LN and OW groups with no differences in BA-FMD. Increases in FA-BF and FA-VC were attenuated during the last stage of plantarflexion exercise at 30% of 1RM in OB (both P < 0.001) compared to LN and OW, while upper-body exercise vasodilation was unchanged. FA-BF and FA-VC during plantarflexion exercise were correlated to FA-FMD (FA-BF: r = 0.423, P = 0.007, FA-VC: r = 0.367, P = 0.021) and BMI (FA-BF: r = -0.386, P = 0.015, FA-VC: r = -0.456, P = 0.004). Postmenopausal females with OB have reduced lower-limb endothelial and exercise vasodilator function during submaximal dynamic plantarflexion exercise compared to LN and OW. Our findings indicate that obesity may predict diminished leg endothelial function, BF and VC during exercise in postmenopausal females.

Walnuts for the eye and vision

The increase in lifespan with the consequent expansion of the aging of the world population has become an important challenge for public health. In recent decades, there has been a progressive increase in the incidence of debilitating diseases related to aging, including neurodegenerative disorders and eye diseases. Oxidative stress and inflammation are believed to play a critical role in several eye disorders, such as age‐related macular degeneration (AMD), diabetic retinopathy (DR), and cataracts, the leading causes of visual loss and blindness worldwide. Neurodegenerative events were also related to AMD and DR.Nutrients such as n‐3 polyunsaturated fatty acids (n‐3 PUFA) and antioxidants, specifically polyphenols, carotenoids, and vitamins C and E, may play a role in preventing both cognitive decline and retinal degenerative processes. Nuts have been described as a “superfood”, containing a notable variety of natural components that may have additive and/or synergistic properties for health and may prevent some pathologies. Nuts in general and walnuts in particular have a rich matrix of these bioactive components and through additive effects, have the potential to beneficially impact neuronal function in the brain and retina. Among different nuts, walnuts contain n‐3 PUFAs, specifically α‐linolenic acid (ALA; C18:3n‐3). It is believed that ALA may improve brain health indirectly through conversion to docosahexaenoic acid (DHA; C22:6n‐3), which has the ability to modulate brain plasticity and counteracts neuroinflammation in experimental studies. Other bioactive compounds in walnuts, such as arginine, tocopherols, folate, melatonin and polyphenols, also support neurological health and cognitive well‐being by modulating blood pressure, HDL function, glucoregulation, endothelial vasodilator function, oxidative status and vascular dysfunction. Polyphenols (including ellagitannins) have high antioxidant and prebiotic properties, which can regulate the gut microbiome, which is related to the increased risk of several inflammatory diseases. There is growing evidence that walnuts may contribute positively to eye disorders such as AMD, DR, and cataract prevention.

Roles of endothelial and smooth muscle cell dysfunction and vasa vasorum in vasomotor disorders in ischemia with no obstructive coronary artery disease

Recently, the importance has emerged of ischemia with no obstructive coronary artery disease (INOCA), for which endothelial and vascular smooth muscle cell (VSMC) dysfunctions and alterations in coronary vasa vasorum are involved. Regarding endothelial vasodilator functions, both endothelium-derived nitric oxide and endothelium-derived hyperpolarizing factor play important roles in modulating vascular tone, especially in the microcirculation. Recent studies have suggested systemic endothelial dysfunction in INOCA. Regarding VSMC dysfunction, Rho-kinase has been identified as a key molecular mechanism of VSMC hyperconstriction in INOCA. Finally, recent advances of coronary imaging have demonstrated the important role of altered adventitial vasa vasorum functions in INOCA.

Circulating endothelial cells as a marker of endothelial dysfunction in patients with psoriatic arthritis

Abstract. Psoriatic arthritis (PsA) is a chronic progressive inflammatory disease that involves damage of the skin and joints and leads to the development of cardiopulmonary diseases. Mortality among this cohort is 1.28 times higher than the population level. The presence of a prolonged systemic inflammatory process is a significant predictor of the development of cardiovascular (CV) diseases due to the progression of endothelial dysfunction (ED). Objective. To evaluate the role of circulating endothelial cell (CEC) levels as a marker of endothelial dysfunction in patients with psoriatic arthritis. Materials and Methods. We examined 97 patients diagnosed with PsA and 25 clinically healthy patients who formed the control group. All patients underwent diagnostic methods characterizing the course of the disease, assessment of endothelium-dependent vasodilation (EDVD) in response to reactive hyperaemia and CEC levels. Results. The results of the study of endothelial function in patients with PsA demonstrated that reduced EDVD (less than 10 %) was more common among patients with PsA compared to the control group (75.3 % vs. 11.8 %, respectively). The analysis of the CEC content in peripheral blood showed a significant difference (7.15 ± 0.19 and 4.05 ± 0.11, respectively, p &lt; 0.001) between patients with PsA and the control group. In addition, were established the relationships between endothelial dysfunction and the state of endothelial vasodilatory function (rs = -0.91, p &lt; 0.05), disease duration (rs = 0.69, p &lt; 0.05), disease activity (DAPSA (rs = 0.65, p &lt; 0.05), inflammatory process itself (ESR (rs = 0.39, p &lt; 0.05), CRP (rs = 0.52, p &lt; 0.05) and skin lesion prevalence (PASI (rs = - 0.42, p &lt; 0.05)). Conclusions. Our studies suggest a significant prevalence of ED in patients with PsA. The high values of negative correlation between EDVD and CEC are quite expected and comparable to modern studies and allow us to consider desquamated endothelial cells as an independent marker for assessing the state of the endothelium in patients with PsA and are consistent with the literature.

Phosphorylated PKM2 regulates endothelium-dependent vasodilation in diabetes.

Endothelium-dependent vasodilation dysfunction is the pathological basis of diabetic macroangiopathy. The utilization and adaptation of endothelial cells to high glucose determine the functional status of endothelial cells. Glycolysis pathway is the major energy source for endothelial cells. Abnormal glycolysis plays an important role in endothelium-dependent vasodilation dysfunction induced by high glucose. Pyruvate kinase isozyme type M2 (PKM2) is one of key enzymes in glycolysis pathway, phosphorylation of PKM2 can reduce the activity of pyruvate kinase and affect the glycolysis process of glucose. TEPP-46 can stabilize PKM2 in its tetramer form, reducing its dimer formation and phosphorylation. Using TEPP-46 as a tool drug to inhibit PKM2 phosphorylation, this study aims to explore the impact and potential mechanism of phosphorylated PKM2 (p-PKM2) on endothelial dependent vasodilation function in high glucose, and to provide a theoretical basis for finding new intervention targets for diabetic macroangiopathy. The mice were divided into 3 groups: a wild-type (WT) group (a control group, C57BL/6 mice) and a db/db group (a diabetic group, db/db mice), which were treated with the sodium carboxymethyl cellulose solution (solvent) by gavage once a day, and a TEPP-46 group (a treatment group, db/db mice+TEPP-46), which was gavaged with TEPP-46 (30 mg/kg) and sodium carboxymethyl cellulose solution once a day. After 12 weeks of treatment, the levels of p-PKM2 and PKM2 protein in thoracic aortas, plasma nitric oxide (NO) level and endothelium-dependent vasodilation function of thoracic aortas were detected. High glucose (30 mmol/L) with or without TEPP-46 (10 μmol/L), mannitol incubating human umbilical vein endothelial cells (HUVECs) for 72 hours, respectively. The level of NO in supernatant, the content of NO in cells, and the levels of p-PKM2 and PKM2 protein were detected. Finally, the effect of TEPP-46 on endothelial nitric oxide synthase (eNOS) phosphorylation was detected at the cellular and animal levels. Compared with the control group, the levels of p-PKM2 in thoracic aortas of the diabetic group increased (P<0.05). The responsiveness of thoracic aortas in the diabetic group to acetylcholine (ACh) was 47% lower than that in the control group (P<0.05), and that in TEPP-46 treatment group was 28% higher than that in the diabetic group (P<0.05), while there was no statistically significant difference in the responsiveness of thoracic aortas to sodium nitroprusside (SNP). Compared with the control group, the plasma NO level of mice decreased in the diabetic group, while compared with the diabetic group, the phosphorylation of PKM2 in thoracic aortas decreased and the plasma NO level increased in the TEPP-46 group (both P<0.05). High glucose instead of mannitol induced the increase of PKM2 phosphorylation in HUVECs and reduced the level of NO in supernatant (both P<0.05). HUVECs incubated with TEPP-46 and high glucose reversed the reduction of NO production and secretion induced by high glucose while inhibiting PKM2 phosphorylation (both P<0.05). At the cellular and animal levels, TEPP-46 reversed the decrease of eNOS (ser1177) phosphorylation induced by high glucose (both P<0.05). p-PKM2 may be involved in the process of endothelium-dependent vasodilation dysfunction in Type 2 diabetes by inhibiting p-eNOS (ser1177)/NO pathway.

Pharmacological effects of a new soluble guanylate cyclase stimulator in experimental pulmonary arterial hypertension

Aim. To assess the effect of an indolinone derivative (2-[2-[(5RS)-5-(hydroxymethyl)-3-methyl-1,3-oxazolidine-2yliden]-2-cyanoethylidene]-1H-indole-3(2H)-one (codename – GRS) on right ventricular contractility, endothelial vasodilator function, and histologic changes in the lungs and heart in a rat model of monocrotaline-induced pulmonary hypertension.Materials and methods. Pulmonary arterial hypertension (PAH) was induced in Wistar rats by a single subcutaneous administration of monocrotaline at a dose of 60 mg / kg. Starting from day 15 after PAH induction, the rats received either GRS at a dose of 10 mg / kg or riociguat at a dose of 1 mg / kg orally once a day. Blood pressure in the right ventricle, right ventricular weight, endothelial vasodilator function, and the histologic structure of the lungs and heart were studied after the last administration of test substances.Results. Twenty-eight days after monocrotaline administration, the rats developed PAH, as shown by the increase in the maximal blood pressure in the right ventricle and the right ventricular weight / total heart weight ratio. GRS after multiple administration reduced the maximal blood pressure in the right ventricle, had no significant effect on its contractility, improved endothelial vasodilator function, and normalized blood pressure. Riociguat had a hypotensive effect and did not alleviate endothelial dysfunction in experimental PAH.Conclusion. The indolinone derivative GRS and riociguat, both soluble guanylate cyclase stimulators, lowered blood pressure in the right ventricle. GRS also alleviated endothelial dysfunction in animals with experimental PAH.

Impaired β 2 -adrenergic endothelium-dependent vasodilation in patients previously hospitalized with coronavirus disease 2019.

The pulse wave response to salbutamol (PWRS) - change in augmentation index (AIx) - provides a means to assess endothelial vasodilator function in vivo . Endothelial dysfunction plays a relevant role in the pathogenesis of hypertension and cardiovascular disease and appears to underlie many of the complications of coronavirus disease 2019 (COVID-19). However, to what degree this persists after recovery is unknown. Individuals previously hospitalized with COVID-19, those recovered from mild symptoms and seronegative controls with well known risk factors for endothelial dysfunction were studied. To assess the involvement of nitric oxide-cyclic guanosine monophosphate pathway (NO-cGMP) on PWRS, sildenafil was also administrated in a subsample. One hundred and one participants (60 men) aged 47.8 ± 14.1 (mean ± SD) years of whom 33 were previously hospitalized with COVID-19 were recruited. Salbutamol had minimal effect on haemodynamics including blood pressure and heart rate. It reduced AIx in controls ( n = 34) and those recovered from mild symptoms of COVID-19 ( n = 34) but produced an increase in AIx in those previously hospitalized: mean change [95% confidence interval] -2.85 [-5.52, -0.188] %, -2.32 [-5.17,0.54] %, and 3.03 [0.06, 6.00] % for controls, those recovered from mild symptoms and those previously hospitalized, respectively ( P = 0.001). In a sub-sample ( n = 22), sildenafil enhanced PWRS (change in AIx 0.05 [-2.15,2.24] vs. -3.96 [-7.01. -2.18], P = 0.006) with no significant difference between hospitalized ( n = 12) and nonhospitalized participants ( n = 10). In patients previously hospitalized with COVID-19, there is long-lasting impairment of endothelial function as measured by the salbutamol-induced stimulation of the NO-cGMP pathway that may contribute to cardiovascular complications.

Endothelial cell vasodilator dysfunction mediates progressive pregnancy-induced hypertension in endothelial cell tetrahydrobiopterin deficient mice

Background and purposePregnancy-associated vascular remodelling is essential for both maternal and fetal health. We have previously shown that maternal endothelial cell tetrahydrobiopterin (BH4) deficiency causes poor pregnancy outcomes. Here, we investigated the role and mechanisms of endothelial cell-mediated vasorelaxation function in these outcomes. Experimental approachThe vascular reactivity of mouse aortas and uterine arteries from non-pregnant and pregnant endothelial cell-specific BH4 deficient mice (Gch1fl/flTie2cre mice) was assessed by wire myography. Systolic blood pressure was assessed by tail cuff plethysmography. Key resultsIn late pregnancy, systolic blood pressure was significantly higher (∼24 mmHg) in Gch1fl/flTie2cre mice compared with wild-type littermates. This was accompanied by enhanced vasoconstriction and reduced endothelial-dependent vasodilation in both aorta and uterine arteries from pregnant Gch1fl/flTie2cre mice. In uterine arteries loss of eNOS-derived vasodilators was partially compensated by upregulation of intermediate and large-conductance Ca2+-activated K+ channels. In rescue experiments, oral BH4 supplementation alone did not rescue vascular dysfunction and pregnancy-induced hypertension in Gch1fl/flTie2cre mice. However, combination with the fully reduced folate, 5-methyltetrahydrofolate (5-MTHF), restored endothelial cell vasodilator function and blood pressure. Conclusions and implicationsWe identify a critical requirement for maternal endothelial cell Gch1/BH4 biosynthesis in endothelial cell vasodilator function in pregnancy. Targeting vascular Gch1 and BH4 biosynthesis with reduced folates may provide a novel therapeutic target for the prevention and treatment of pregnancy-related hypertension.

Clinical value of the platelet and inflammatory factor activation in vascular endothelial injury in essential hypertension.

To investigate the clinical value of platelet and inflammatory factor activation in vascular endothelial injury in hypertension. A total of 120 hypertension patients diagnosed in our hospital from December 2019 to June 2021 were enrolled as study objects (Hypertension group); besides, another cohort of 60 healthy people undergoing physical examination at the same period were recruited as the controls (Control group). Next, the baseline clinical characteristics of subjects in the two groups were recorded and compared. Specifically, a hematology analyzer was adopt for detecting the mean platelet volume (MPV), platelet distribution width (PDW) and platelet hematocrit (PCT); ELISA for the level of IL-6, IL-8 and TNF-α; PHILIPS EPIQ 7 C (a device assessing endothelial vasodilator function in a non-invasive fashion) for reactive hyperemia index (RHI); univariate and multivariate regression analysis for risk factors triggering endothelial dysfunction; and Spearman correlation analysis for the correlation of platelet activation indicators and inflammatory factor level with vascular endothelial function. Compared with the Control group, the patients in the Hypertension group exhibited higher levels of MPV, PDW, PCT, inflammatory factors (IL-6, IL-8 and TNF-α) and lower RHI. Moreover, Spearman correlation analysis showed a significant negative correlation of MPV, PDW, PCT, IL-6, IL-8 and TNF-α level with RHI level. In addition, univariate and multivariate regression analysis presented that MPV, PCT, IL-8 and TNF-α were risk factors for vascular endothelial dysfunction. The activation of platelet and inflammatory factor is closely related to vascular endothelial function injury in patients with hypertension. To be specifically, platelet and inflammatory factor activation can effectively reflect the vascular endothelial function injury in patients with hypertension and has high clinical value.

Chronic snus use in healthy males alters endothelial function and increases arterial stiffness.

BackgroundSnus usage is commonly touted as a safer alternative to cigarette smoking. However, recent studies have demonstrated possible adverse cardiovascular effects in chronic snus users. The present study evaluates the effects of chronic snus use on vascular function by assessing central arterial stiffness and endothelial vasodilatory function in healthy chronic snus users as compared to matched non-users.Methods and resultsFifty healthy males (24 snus users, 26 age-matched controls) with a mean age of 44 years were included in the study. Arterial stiffness was assessed employing both pulse wave velocity and pulse wave analysis. Endothelial vasodilatory function was measured by venous occlusion plethysmography, utilizing intra-arterial administration of acetylcholine, glyceryl trinitrate and bradykinin to further gauge endothelium-dependent and -independent vasodilatory function. Arterial stiffness was significantly higher in chronic snus users as compared to controls: pulse wave velocity [m/s]: 6.6±0.8 vs 7.1±0.9 resp. (p = 0.026), augmentation index corrected for heart rate [%]: 0.1±13.2 vs 7.3±7.8 resp. (p = 0.023). Endothelial independent vasodilation, i.e. the reaction to glyceryl trinitrate, was significantly lower in snus users as measured by venous occlusion plethysmography.ConclusionsThe results of this study show an increased arterial stiffness and an underlying endothelial dysfunction in daily snus users as compared to matched non-tobacco controls. These findings indicate that long-term use of snus may alter the function of the endothelium and therefore reinforces the assertion that chronic snus use is correlated to an increased risk of development of cardiovascular disease.

Microvascular Function in Skeletal Muscle of Adiponectin Knockout Mice

Adiponectin is known to be an important regulator of both metabolic and vascular function in skeletal muscle; however, a direct role for adiponectin in exercise training‐induced microvascular adaptation of skeletal muscle has not been documented. We assessed oxidative metabolism, capillarity, and endothelium‐dependent vasodilation in soleus and gastrocnemius muscles of sedentary and exercise trained, wild type (WT) and adiponectin knockout (AdipoKO) mice. WT and AdipoKO mice were obtained at 10‐12 wks of age and underwent treadmill exercise training (1 hr/day, 5 days/wk for 8 wks) or remained sedentary in cages. In sedentary mice, citrate synthase activity and capillarity were increased in soleus muscle of AdiopKO mice as compared to WT mice. In soleus muscle feed arteries from sedentary mice, endothelium‐dependent vasodilation to acetylcholine was reduced in AdipoKO mice as compared to WT mice. Exercise training increased capillarity and citrate synthase activity in soleus muscle of WT mice, but not AdipoKO mice. Exercise training did not alter endothelium‐dependent dilation in soleus feed arteries from either AdipoKO or WT mice. In 1A arterioles from the gastrocnemius muscle of sedentary mice, endothelium‐dependent vasodilation to acetylcholine was not altered in AdipoKO compared to WT mice; however, exercise training increased endothelium‐dependent vasodilation to acetylcholine in WT, but not AdipoKO mice. These data suggest that deletion of adiponectin and a reduction of endothelial vasodilatory function stimulates a compensatory increase in oxidative capacity and capillarity in soleus muscle; however, no further increase in these parameters occurs in soleus muscle of AdipoKO mice in response to exercise training. In contrast, in gastrocnemius muscle, endothelial vasodilatory function was not affected by deletion of adiponectin in sedentary mice, but endothelium‐dependent vasodilation of 1A arterioles increased in response to exercise training in WT, but not in AdipoKO mice. Taken together, these data suggest that the role of adiponectin in adaptation of metabolic and microvascular function in response to exercise training is muscle‐specific.

Abstract 136: Vascular Impairment From Acute Exposure To E-cigarette Aerosol Is Rescued By Inhibition Of The Receptor For Advanced Glycation End Products (RAGE)

Introduction: E-cigarette use is known to induce vascular impairment by altering vasomotor and cellular functions of the vascular wall, but the molecular mechanism of e-cigarette-induced vascular impairment is largely unexplored. We investigated whether inhibition of RAGE prevents impairment of vasomotor function from acute e-cigarette exposure Hypothesis: Impairment of endothelial vasodilatory function requires the activation of RAGE. Methods: Anesthetized rats (n=8/group) were exposed to aerosols from flavorless tank style e-cigarettes with and without freebase nicotine (12 mg/ml) or air in a single session of 10 cycles of pulsatile 5s exposure over 5 minutes. For each exposure condition, groups received either 1 mg/kg of RAGE inhibitor FPS-ZM1 or vehicle i.p. 1 hour before exposure (i.e., total of 6 groups). Femoral artery flow-mediated dilation (FMD) was measured using micro-ultrasound before and after exposure. Results: Exposure to e-cigarette aerosol with and without nicotine impaired FMD in vehicle groups (8.3±2.7% pre-exposure vs 4.7±2.4% post-exposure, p=0.01; 9.3±4.6% pre- vs 4.8±2.7% post-, p=0.03, respectively), with no change in air control (9.7±3.2% pre- vs 9.3±3.5% post-, p=0.81). Post-exposure FMD in both aerosol groups with vehicle was lower than that in the air group with vehicle (p=0.01 for each aerosol vs air). However, FPS-ZM1 prevented the FMD impairment by aerosol exposure (with nicotine 9.1±3.5% pre- vs 8.9±2.1% post-, p=0.90; without nicotine 9.5±4.3% pre- vs 7.1±2.0% post-, p=0.17), with no change in air control (7.6±2.7% pre- vs 7.4±3.1% post-, p=0.86). Post-exposure FMD values in both aerosol groups receiving FPS-ZM1 were comparable to the air control (p=0.4 and 0.8, respectively). There were no significant difference in post-exposure FMD in the air groups receiving FPS-ZM1 or vehicle (p&gt;0.99). Conclusions: RAGE mediates e-cigarette-induced acute impairment of endothelial vasodilatory function.

JUUL™ing and Heating Lead to a Worsening of Arterial Stiffness.

Background: The widespread use of the JUUL™ device ignited a discussion about the effects these products have on harm reduction. Therefore, we conducted a study directly comparing the JUUL™ device with a cigarette, a heated tobacco product, and a nicotine-free e-cigarette to examine the acute effects on arterial stiffness. Methods: This crossover-designed study examines 20 occasional smokers (age 25.2 ± 2.5 years). Study participants used each of the four smoking devices for a duration of 5 min following a protocol. Peripheral blood pressure and parameters of arterial stiffness and endothelial vasodilator function such as the reactive hyperemia index and the augmentation index were measured using the EndoPAT™2000 before and after. Results: In addition to significant peripheral hemodynamic changes after 5 and 10 min (p < 0.05), the reactive hyperemia index showed a significant decrease for all devices 15 min after consumption and remained significantly decreased after 60 min (p < 0.01). The augmentation index adjusted for a heart rate of 75 bpm increased significantly for all devices 15 and 60 min after consumption (p < 0.01). Conclusions: In conclusion, the increases in blood pressure and arterial stiffness are similar after smoking, JUUL™ing, heating, and vaping. These changes may be associated with an increase in cardiovascular risks; however, an evaluation of the long-term effects of JUUL™ing, vaping and heating is needed.

418 Activation of the Glucagon-Like Peptide-1 Pathway in Obese Pre-Diabetic Individuals Improves Endothelial Function Independently of Weight Loss

OBJECTIVES/GOALS: We aimed to determine if GLP-1 receptor agonists exert beneficial effects on surrogate measures of cardiovascular function independently of weight loss. Our objective was to compare the outcomes between GLP-1 receptor agonist treatment versus a similar drug without cardiovascular benefit versus weight loss through diet alone. METHODS/STUDY POPULATION: We enrolled 88 individuals with obesity (BMI ≥ 30kg/m2) and pre-diabetes and randomized them in a 2:1:1 ratio to 14 weeks of the GLP-1 receptor agonist liraglutide, the dipeptidyl peptidase-4 inhibitor sitagliptin, or hypocaloric diet. Sitagliptin blocks degradation of endogenous GLP-1 but does not cause weight loss or lower adverse cardiovascular outcomes. Treatment was double-blinded and placebo-controlled for drug, and unblinded for diet. Primary endpoints were flow-mediated dilation (FMD) to assess endothelial vasodilatory function, and plasminogen activator inhibitor-1 (PAI-1) to assess endothelial fibrinolytic function. We used a general linear model for each outcome and included gender as a covariate for FMD. Baseline characteristics were similar. Mean age was 50, with 32% men and 13% black. RESULTS/ANTICIPATED RESULTS: At 14 weeks, diet and liraglutide caused weight loss (diet -4.3 ± 3.2 kg, P&lt;0.01; liraglutide -2.7 ± 3.2, P&lt;0.01), while sitagliptin did not (-0.7 ± 2.0, P=0.17). Diet did not improve FMD at 14 weeks compared to baseline (+0.9%, 95% CI [-1.5, 3.3], P=0.46). FMD tended to increase after liraglutide and sitagliptin but was not significant (liraglutide +1.2 [-0.3, 2.8], P=0.12; sitagliptin +1.6 [-0.6, 3.8], P=0.15). Given that liraglutide and sitagliptin work through the same GLP-1 pathway, we combined the liraglutide and sitagliptin groups for overall effect on FMD, which was significantly improved from baseline (+1.4 [0.1, 2.8], P=0.04). Diet and liraglutide improved PAI-1 at 14 weeks (diet -4.4U/mL, [-8.5, -0.2], P=0.04; liraglutide -3.4 [-6.0, -0.7], P=0.01), while sitagliptin did not (-1.4 [-5.1, 2.3], P=0.46). DISCUSSION/SIGNIFICANCE: Activation of the GLP-1 pathway by liraglutide or sitagliptin improves FMD independent of weight loss, while PAI-1 improvement is weight-loss dependent and is only seen after liraglutide or diet. Our study suggests the cardiovascular benefit of liraglutide may be due to combined improvements in endothelial vasodilatory and fibrinolytic function.

Endothelial dysfunction in COVID-19 patients assessed with Endo-PAT2000.

It has been widely reported that the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) attaches human cells by using the Angiotensin Converting Enzyme 2 (ACE2) receptor, but vascular impairment described during coronavirus disease 2019 (COVID-19) infection is primarily due to the direct involvement of the endothelial cells by the virus or secondarily to the inflammatory host response is currently unknown. We therefore aimed to demonstrate in vivo the presence of endothelial dysfunction in six COVID-19 patients without cardiovascular risk factors or pre-existing cardiac condition, using the Endo-PAT 2000, a device able to measure endothelial vasodilation function in a rapid and non-invasive way. Four patients were positive for endothelial dysfunction, with RHI values between 1.13-1.56 (average value 1.32, normal values >1.67); in one of the two negative patients the reported RHI value was slightly above the cutoff (1.72). Our findings confirm that COVID-19 patients are at higher risk of developing endothelial dysfunction. In addition, our results demonstrate that endothelial impairment may occur even in the absence of cardiovascular risk factors.

HDL functionality in type 1 and type 2 diabetes: new insights.

Purpose of reviewTo critically appraise new insights into HDL structure and function in type 1 diabetes (T1DM) and type 2 diabetes (T2DM).Recent findingsIn young T1DM patients with early renal impairment and a high inflammatory score, both HDL antioxidative activity and endothelial vasodilatory function were impaired, revealing a critical link between HDL dysfunction, subclinical vascular damage, systemic inflammation and end organ damage. HDL may inhibit development of T2DM by attenuating endoplasmic reticulum (ER) stress and apoptotic loss of pancreatic β-cells, an effect due in part to ABC transporter-mediated efflux of specific oxysterols with downstream activation of the hedghehog signalling receptor, Smoothened. The apoM-sphingosine-1-phosphate complex is critical to HDL antidiabetic activity, encompassing protection against insulin resistance, promotion of insulin secretion, enhanced β-cell survival and inhibition of hepatic glucose production. Structure-function studies of HDL in hyperglycemic, dyslipidemic T2DM patients revealed both gain and loss of lipidomic and proteomic components. Such changes attenuated both the optimal protective effects of HDL on mitochondrial function and its capacity to inhibit endothelial cell apoptosis. Distinct structural components associated with individual HDL functions.SummaryExtensive evidence indicates that both the proteome and lipidome of HDL are altered in T1DM and T2DM, with impairment of multiple functions.

The protective role of neuronal nitric oxide synthase in endothelial vasodilation in chronic β-adrenoceptor overstimulation

AimsNitric oxide synthases (NOSs) are key enzymes regulating vascular function. Previously, we reported that β-adrenergic (β-AR) overstimulation, a common feature of cardiovascular diseases, did not impair endothelium-dependent vasodilation, although it resulted in endothelial NOS (eNOS) uncoupling and reduced NO bioavailability. In addition to NO, neuronal NOS (nNOS) produces H2O2, which contributes to vasodilation. However, there is limited information regarding vascular β-AR signaling and nNOS. In the present study, we assessed the possible role of nNOS-derived H2O2 and caveolins on endothelial vasodilation function following β-AR overstimulation. Main methodsMale C57BL/6 wild-type and nNOS knockout mice (nNOS−/−) were treated with the β-AR agonist isoproterenol (ISO, 15 mg·kg−1·day−1, s.c.) or vehicle (VHE) for seven days. Relaxation responses of aortic rings were evaluated using wire myograph and H2O2 by Amplex Red. Key findingsAcetylcholine- or calcium ionophore A23187-induced endothelium-dependent relaxation was similar in aortic rings from VHE and ISO. However, this relaxation was significantly reduced in aortas from ISO compared to VHE when (1) caveolae were disrupted, (2) nNOS was pharmacologically inhibited or genetically suppressed and (3) H2O2 was scavenged. NOS-derived H2O2 production was higher in the aortas of ISO mice than in those of VHE mice. Aortas from ISO-treated mice showed increased expression of caveolin-1, nNOS and catalase, while caveolin-3 expression did not change. SignificanceThe results suggest a role of caveolin-1 and the nNOS/H2O2 vasodilatory pathway in endothelium-dependent relaxation following β-AR overstimulation and reinforce the protective role of nNOS in cardiovascular diseases associated with high adrenergic tone.

Negative Influence of Insufficient Sleep on Endothelial Vasodilator and Fibrinolytic Function in Hypertensive Adults.

[Figure: see text].