Cardiovascular disrupting effects of bisphenols, phthalates, and parabens related to endothelial dysfunction: Review of toxicological and pharmacological mechanisms.

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. CVDs are promoted by the accumulation of lipids and immune cells in the endothelial space resulting in endothelial dysfunction. Endothelial cells are important components of the vascular endothelium, that regulate the vascular flow. The imbalance in the production of vasoactive substances results in the loss of vascular homeostasis, leading the endothelial dysfunction. Thus, endothelial dysfunction plays an essential role in the development of atherosclerosis and can be triggered by different cardiovascular risk factors. On the other hand, the 17ß-estradiol (E2) hormone has been related to the regulation of vascular tone through different mechanisms. Several compounds can elicit estrogenic actions similar to those of E2. For these reasons, they have been called endocrine-disrupting compounds (EDCs). This review aims to provide up-to-date information about how different EDCs affect endothelial function and their mechanistic roles in the context of CVDs.

Mesenteric artery smooth muscle cells from hypertensive rats have increased microtubule acetylation.

The dynamic nature of the microtubule network is dependent in part by post-translational modifications (PTMs) - particularly through acetylation, which stabilizes the microtubule network. Whether PTMs of the microtubule network in vascular smooth muscle cells (VSMCs) contribute to the pathophysiology of hypertension is unknown. The aim of this study was to determine the acetylated state of the microtubule network in the mesenteric arteries of spontaneously hypertensive rats (SHR). Experiments were performed on male normotensive rats and SHR mesenteric arteries. Western blotting and mass spectrometry determined changes in tubulin acetylation. Wire myography was used to investigate the effect of tubacin on isoprenaline-mediated vasorelaxations. Isolated cells from normotensive rats were used for scanning ion conductance microscopy (SICM). Mass spectrometry and Western blotting showed that tubulin acetylation is increased in the mesenteric arteries of the SHR compared with normotensive rats. Tubacin enhanced the ß-adrenoceptor-mediated vasodilatation by isoprenaline when the endothelium was intact, but attenuated relaxations when the endothelium was denuded or nitric oxide production was inhibited. By pre-treating vessels with colchicine to disrupt the microtubule network, we were able to confirm that the effects of tubacin were microtubule-dependent. Using SICM, we examined the cell surface Young's modulus of VSMCs, but found no difference in control, tubacin-treated, or taxol-treated cells. Acetylation of tubulin at Lys40 is elevated in mesenteric arteries from the SHR. Furthermore, this study shows that tubacin has an endothelial-dependent bimodal effect on isoprenaline-mediated vasorelaxation.

Acute inspiratory resistance training enhances endothelium-dependent dilation and retrograde shear rate in healthy young adults.

Inspiratory resistance training (IRT) yields significant reductions in resting blood pressure and improves vascular endothelial function. Our objective was to quantify the acute effects of IRT on brachial artery flow-mediated dilation (FMD) and shear rates (SRs) in healthy men and women. Twenty young adults (22.9 ± 3.4 years; 10 male, 10 female) completed a single bout of IRT or Rest condition in a randomized crossover design. Brachial artery FMD was performed before, 10 min after, and 40 min after the assigned condition. Brachial artery blood flow velocities were collected during IRT, separated by breathing cycle phase, and converted into SRs. FMD improved 10 min post-IRT (+1.86 ± 0.61%; p = 0.025) but returned to baseline by 40 min post-IRT (p = 0.002). Anterograde SR decreased by 10% and retrograde SR increased 102% during resisted inspiration, relative to baseline SR (p < 0.001). Anterograde SR increased by 7% in men and women (p < 0.001) and retrograde SR decreased by 12% in women but not men (p = 0.022) during unresisted expiration, relative to baseline SR. A single bout of IRT elicits a transient enhancement in FMD in both men and women. Acute IRT-related enhancements in SRs may contribute to sustained improvements in FMD that have been reported previously.

Statin administration improves vascular function in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is characterized by impaired vascular endothelial function that may be improved by hydroxy-methylglutaryl-CoA (HMG-CoA) reductase enzyme inhibition. Thus, using a parallel, double-blind, placebo-controlled design, this study evaluated the efficacy of 30-day atorvastatin administration (10 mg daily) on peripheral vascular function and biomarkers of inflammation and oxidative stress in 16 patients with HFpEF [Statin: n = 8, 74 ± 6 yr, ejection fraction (EF) 52-73%; Placebo: n = 8, 67 ± 9 yr, EF 56-72%]. Flow-mediated dilation (FMD) and sustained-stimulus FMD (SS-FMD) during handgrip (HG) exercise, reactive hyperemia (RH), and blood flow during HG exercise were evaluated to assess conduit vessel function, microvascular function, and exercising muscle blood flow, respectively. FMD improved following statin administration (pre, 3.33 ± 2.13%; post, 5.23 ± 1.35%; P < 0.01), but was unchanged in the placebo group. Likewise, SS-FMD, quantified using the slope of changes in brachial artery diameter in response to increases in shear rate, improved following statin administration (pre: 5.31e-5 ± 3.85e-5 mm/s-1; post: 8.54e-5 ± 4.98e-5 mm/s-1; P = 0.03), with no change in the placebo group. Reactive hyperemia and exercise hyperemia responses were unchanged in both statin and placebo groups. Statin administration decreased markers of lipid peroxidation (malondialdehyde, MDA) (pre, 0.652 ± 0.095; post, 0.501 ± 0.094; P = 0.04), whereas other inflammatory and oxidative stress biomarkers were unchanged. Together, these data provide new evidence for the efficacy of low-dose statin administration to improve brachial artery endothelium-dependent vasodilation, but not microvascular function or exercising limb blood flow, in patients with HFpEF, which may be due in part to reductions in oxidative stress.NEW & NOTEWORTHY This is the first study to investigate the impact of statin administration on vascular function and exercise hyperemia in patients with heart failure with preserved ejection fraction (HFpEF). In support of our hypothesis, both conventional flow-mediated dilation (FMD) testing and brachial artery vasodilation in response to sustained elevations in shear rate during handgrip exercise increased significantly in patients with HFpEF following statin administration, beneficial effects that were accompanied by a decrease in biomarkers of oxidative damage. However, contrary to our hypothesis, reactive hyperemia and exercise hyperemia were unchanged in patients with HFpEF following statin therapy. These data provide new evidence for the efficacy of low-dose statin administration to improve brachial artery endothelium-dependent vasodilation, but not microvascular reactivity or exercising muscle blood flow in patients with HFpEF, which may be due in part to reductions in oxidative stress.

Does perceived caloric and nutrient intake influence the acute effect of beverage consumption on cardiovascular function?

Our objective was to explore whether consuming the same high-fat/sugar beverage affects endothelial function differently depending on whether it is presented as "unhealthy" [accurate high calorie (kcal), fat, and sugar information displayed] versus "healthy" (inaccurate low kcal, fat, and sugar information displayed). Twenty-five, young (21 ± 2 yr), healthy, food-stress/shame-prone women completed three conditions: milkshake consumption (540 kcal, 80 g sugar, and 14 g fat) where correct, "unhealthy" nutritional information was shown to participants (milkshake condition), consumption of the same milkshake but with incorrect, "healthy" information shown to participants (100 kcal, 3 g sugar, and 4 g fat; sham-nutrishake condition), and water consumption (control condition). Pre- and postbeverage we assessed 1) endothelial function via standard brachial artery flow-mediated dilation (FMD); 2) perceived shame, stress, beverage healthiness, and harm; and 3) blood (plasma) glucose, insulin, triglycerides and oral fluid cortisol, and tumor necrosis factor-alpha (TNFα) receptor binding. Glucose, triglycerides, and insulin increased in the milkshake and sham-nutrishake conditions (P < 0.05). The milkshake was perceived as less healthy (P < 0.001) and more harmful (P < 0.001) than the sham-nutrishake. Shame, stress, oral fluid cortisol and TNFα receptor binding did not increase postconsumption. FMD decreased after the milkshake condition (pre: 7.4 ± 3.3%; post-60 min: 4.9 ± 2.9%; post-90 min: 4.5 ± 3.1%, P < 0.001) but not the sham-nutrishake (pre: 5.7 ± 2.2%; post-60 min: 5.5 ± 2.6%; post-90 min: 5.0 ± 2.4%, P = 0.43) or control conditions (pre: 7.0 ± 2.6%; post-60 min: 6.6 ± 4.1%; post-90 min: 6.0 ± 3.2%, P = 0.29). Shear rate stimulus covariation did not alter FMD results. Lower perceived beverage healthiness was significantly associated with a greater reduction in FMD (ρ = 0.36, P = 0.002). In conclusion, a high-fat/sugar milkshake reduced FMD only when presented as high in fat, sugar, and calories. This suggests that perceptions about nutritional information contribute to the impact of food intake on endothelial function and that nocebo effects could be involved in cardiovascular disease etiology.NEW & NOTEWORTHY This was the first study to investigate how perceived nutritional content influences the impact of a high-sugar/fat beverage on endothelial function. We found that a high-sugar/fat beverage only reduced endothelial function when it was presented to participants as high in calories, fat, and sugar. This suggests that perceived nutritional information contributes to the impact of high sugar and fat intake on endothelial function.

The vascular response to acute sauna heating is similar in young and middle-aged adults.

Sauna has been linked to a reduction of cardiovascular disease risk and is a promising nonpharmacological treatment for populations at risk of cardiovascular disease. This study examined the vascular response to an acute bout of sauna heating in young and middle-aged individuals. Ten young (25 ± 4 yr, 6 males and 4 females) and eight middle-aged adults (56 ± 4 yr, 4 males and 4 females) underwent 40 min of sauna exposure at 80°C. Esophageal and intramuscular temperatures, brachial and superficial femoral artery blood flow, artery diameter, and shear rates were recorded at baseline and following heat exposure. Brachial artery flow-mediated dilation (FMD) was measured at baseline and following 90 min of recovery. Esophageal and muscle temperatures increased similarly in the young and middle-aged adults by 1.5 ± 0.53 and 1.95 ± 0.70°C, respectively (P < 0.05). The shear rate increased by 170-200% (P < 0.001), while blood flow increased by 180-390% (P < 0.001) in the superficial femoral and brachial arteries, respectively, and did not differ between age groups (P = 0.190-0.899). Systolic blood pressure was reduced from 135 ± 17 to 122 ± 20 mmHg (P = 0.017) in middle-aged participants. These data indicate that young and middle-aged adults have similar vascular responses to acute sauna heating.NEW & NOTEWORTHY Sauna therapy has been shown to improve cardiovascular health and function in older adults and individuals with cardiovascular disease risk factors. Specifically, improvements in vascular function have been reported and have been attributed to the increased hemodynamic stimuli on the vasculature associated with thermal stress. The present study quantified this hemodynamic response to a sauna protocol associated with improved cardiovascular health across the lifespan. Our data show that middle-aged adults have the same shear rate and blood flow response to sauna as young adults.

Evidence for the involvement of TRPV2 channels in the modulation of vascular tone in the mouse aorta.

AIMS: Transient receptor potential vanilloid 2 (TRPV2) channels are expressed in both smooth muscle and endothelial cells and participate in vascular mechanotransduction and sensing of high temperatures and lipids. Nevertheless, the impact of TRPV2 channel activation by agonists on the coordinated and cell-type specific modulation of vasoreactivity is unknown. MAIN METHODS: Aorta from 2- to 4-months-old male Oncins France 1 mice was dissected and mounted in tissue baths for isometric tension measurements. TRPV2 channel expression was assessed by immunofluorescence and western blot in mice aortas and in cultured A7r5 rat aortic smooth muscle cells. KEY FINDINGS: TRPV2 channels were expressed in all three mouse aorta layers. Activation of TRPV2 channels with probenecid evoked endothelium-dependent relaxations through a mechanism that involved activation of smooth muscle Kir and Kv channels. In addition, TRPV2 channel inhibition with tranilast increased endothelium-independent relaxations to probenecid and this effect was abrogated by the KATP channel blocker glibenclamide, revealing that smooth muscle TRPV2 channels induce negative feedback on probenecid relaxations mediated via KATP channel inhibition. Exposure to the NO donor sodium nitroprusside increased TRPV2 channel translocation to the plasma membrane in cultured smooth muscle cells and enhanced negative feedback on probenecid relaxations. SIGNIFICANCE: In conclusion, we present the first evidence that TRPV2 channels may modulate vascular tone through a balance of opposed inputs from the endothelium and the smooth muscle leading to net vasodilation. The fact that TRPV2 channel-induced activity can be amplified by NO emphasizes the pathophysiological relevance of these findings.

Mechanosensing by Vascular Endothelium.

Mechanical forces influence different cell types in our bodies. Among the earliest forces experienced in mammals is blood movement in the vascular system. Blood flow starts at the embryonic stage and ceases when the heart stops. Blood flow exposes endothelial cells (ECs) that line all blood vessels to hemodynamic forces. ECs detect these mechanical forces (mechanosensing) through mechanosensors, thus triggering physiological responses such as changes in vascular diameter. In this review, we focus on endothelial mechanosensing and on how different ion channels, receptors, and membrane structures detect forces and mediate intricate mechanotransduction responses. We further highlight that these responses often reflect collaborative efforts involving several mechanosensors and mechanotransducers. We close with a consideration of current knowledge regarding the dysregulation of endothelial mechanosensing during disease. Because hemodynamic disruptions are hallmarks of cardiovascular disease, studying endothelial mechanosensing holds great promise for advancing our understanding of vascular physiology and pathophysiology.

Skipping breakfast does not accelerate the hyperglycemia-induced endothelial dysfunction but reduces blood flow of the brachial artery in young men.

PURPOSE: Postprandial hyperglycemia is assumed to have a negative impact on flow-mediated dilation (FMD), an index of endothelial function, and blood flow of the peripheral conduit arteries. This study aimed to determine whether the enhancement of postprandial hyperglycemia by skipping breakfast accelerates endothelial dysfunction and reduces the blood flow in the brachial artery in young men. METHODS: Using a randomized cross-over design, ten healthy men completed two trials: with and without breakfast (Eating and Fasting trials, respectively). Venous blood sampling and brachial FMD tests were conducted before, 30, 60, 90, and 120 min after a 75-g oral glucose tolerance test (OGTT). RESULTS: Skipping breakfast boosted post-OGTT glucose levels than having breakfast (P = 0.01). The magnitude of the decrease in FMD via OGTT did not vary between trials (main effect of trial P = 0.55). Although brachial blood flow tended to decrease after OGTT in both trials (interaction and main effect of time P = 0.61 and P = 0.054, respectively), the decrease in blood flow following OGTT was greater in the Fasting trial than in the Eating trial (main effect of trial, mean difference = - 15.8 mL/min [95%CI = - 25.6 to - 6.0 mL/min], P < 0.01). CONCLUSION: Skipping breakfast did not enhance the magnitude of the decrease in FMD following glucose loading, but did accelerate hyperglycemia-induced reduction in brachial blood flow. Current findings suggest that even missing one breakfast has negative impacts on the blood flow regulation of the peripheral conduit arteries in young men who habitually eat breakfast.

Role of TRPV4 on vascular tone regulation in pathophysiological states.

Vascular tone regulation is a key event in controlling blood flow in the body. Endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) help regulate the vascular tone. Abnormal vascular responsiveness to various stimuli, including constrictors and dilators, has been observed in pathophysiological states although EC and VSMC coordinate to maintain the exquisite balance between contraction and relaxation in vasculatures. Thus, investigating the mechanisms underlying vascular tone abnormality is very important in maintaining vascular health and treating vasculopathy. Increased intracellular free Ca2+ concentration ([Ca2+]i) is one of the major triggers initiating each EC and VSMC response. Transient receptor potential vanilloid family member 4 (TRPV4) is a Ca2+-permeable non-selective ion channel, which is activated by several stimuli, and is presented in both ECs and VSMCs. Therefore, TRPV4 plays an important role in vascular responses. Emerging evidence indicates the role of TRPV4 on the functions of ECs and VSMCs in various pathophysiological states, including hypertension, diabetes, and obesity. This review focused on the link between TRPV4 and the functions of ECs/VSMCs, particularly its role in vascular tone and responsiveness to vasoactive substances.

Mechanistic, participant, and movement-related factors that contribute to low-flow-mediated constriction.

Endothelial function is commonly determined via the ultrasound-based flow-mediated dilation (FMD) technique which assesses arterial dilation in response to a hyperemia response following distal cuff occlusion. However, the low-flow-mediated constriction (L-FMC) response during cuff-induced ischemia is often overlooked. L-FMC provides unique information regarding endothelial function, but vascular researchers may be unclear on what this metric adds. Therefore, the objective of this review was to examine the mechanistic determinants and participant-level factors of L-FMC. Existing mechanistic studies have demonstrated that vasoreactivity to low flow may be mediated via non-nitric oxide vasodilators (i.e., endothelial hyperpolarizing factors and/or prostaglandins), inflammatory markers, and enhancement of vasoconstriction via endothelin-1. In general, participant-level factors such as aging and presence of cardiovascular conditions generally are associated with attenuated L-FMC responses. However, the influence of sex on L-FMC is unclear with divergent results between L-FMC in upper versus lower limb vessels. The ability of aerobic exercise to augment L-FMC (i.e., make more negative) is well supported, but there is a major gap in the literature concerning the mechanistic underpinnings of this observation. This review summarizes that while larger L-FMC responses are generally healthy, the impact of interventions to augment/attenuate L-FMC has not included mechanistic measures that would provide insight into non-nitric oxide-based endothelial function. Clarifications to terminology and areas of further inquiry as it relates to the specific pharmacological, individual-level factors, and lifestyle behaviors that impact L-FMC are highlighted. A greater integration of mechanistic work alongside applied lifestyle interventions is required to better understand endothelial cell function to reductions in local blood flow.

Endothelial dysfunction is associated with reduced myocardial mechano-energetic efficiency in drug-naïve hypertensive individuals.

Impaired myocardial mechano-energetics efficiency (MEE) was shown to predict incident heart failure, but pathophysiological mechanisms linking impaired MEE with heart failure have not been elucidated. Endothelial dysfunction is a plausible candidate because it has been associated with heart failure. This study aims to investigate the association between MEE and endothelium-dependent vasodilation, among drug-naïve hypertensive individuals. 198 Drug-naïve hypertensive individuals participating in the CATAnzaro MEtabolic RIsk factors (CATAMERI) study were included. All participants underwent to an oral glucose tolerance test and to an echocardiogram for myocardial LVM-normalized mechano-energetic efficiency (MEEi) measurement. Endothelial-dependent and endothelial-independent vasodilatation were measured by strain-gauge plethysmography during intra-arterial infusion of acetylcholine and sodium nitroprusside, respectively. A multivariate linear regression analysis was conducted to investigate the independent association between maximal endothelial-dependent vasodilation and MEEi. Maximal ACh-stimulated forearm blood flow (FBF) was associated to decreased myocardial MEEi (ß = 0.205, p = 0.002) independently of well-established cardiovascular risk factors including age, sex, BMI, waist circumference, smoking status, total and HDL cholesterol, triglycerides, hsCRP, glucose tolerance status, and HOMA-IR index of insulin resistance. Conversely, no association was observed between SNP-stimulated vasodilation and MEEi. Endothelium-mediated vasodilation may contribute to reduce myocardial MEEi independently of several potential confounders. Because diminished myocardial MEE has been previously associated with incident heart failure, a non-invasive assessment of myocardial MEEi may improve the identification of individuals at higher cardiovascular risk who may benefit from the initiation of pharmacological treatments ameliorating the endothelial dysfunction.

Genetic background influences arterial vasomotor function in male and female mice.

The purpose of this study was to assess the influence of genetic background and sex on nitric oxide (NO)-mediated vasomotor function in arteries from different vascular territories. Vasomotor function was assessed in thoracic aorta, abdominal aorta, carotid arteries, and femoral arteries from the following mouse strains: SJL/J, DBA/2J, NZW/LacJ, and C57BL/6J. Contractile responses were assessed using the α1-adrenergic receptor agonist phenylephrine (PE, 10-9 -10-5 M). Vasorelaxation responses were assessed by examining relaxation to an endothelium-dependent vasodilator acetylcholine (ACh, 10-9 -10-5 M) and an endothelium-independent vasodilator sodium nitroprusside (SNP, 10-9 -10-5 M). To evaluate the role of NO, relaxation responses to ACh and SNP were assessed in the absence or presence of a nitric oxide synthase inhibitor (N omega-nitro-l-arginine methyl ester hydrochloride: 10-4 M). Vasomotor responses to ACh and PE varied across strains and among the arteries tested with some strains exhibiting artery-specific impairment. Results indicated some concentration-response heterogeneity in response to ACh and SNP between vessels from females and males, but no significant differences in responses to PE. Collectively, these findings indicate that vasomotor responses vary by genetic background, sex, and artery type.

Preexercise intermittent passive stretching and vascular function after treadmill exercise.

Acute aerobic exercise stress is associated with decreased endothelial function that may increase the likelihood of an acute cardiovascular event. Passive stretch (PS) elicits improvements in vascular function, but whether PS can be performed before exercise to prevent declines in vascular function remains unknown. This strategy could be directly applicable in populations that may not be able to perform dynamic exercise. We hypothesized that preexercise PS would provide better vascular resilience after treadmill exercise. Sixteen healthy college-aged males and females participated in a single laboratory visit and underwent testing to assess micro- and macrovascular function. Participants were randomized into either PS group or sham control group. Intermittent calf PS was performed by having the foot in a splinting device for a 5-min stretch and 5-min relaxation, repeated four times. Then, a staged V̇o2 peak test was performed and 65% V̇o2 peak calculated for subjects to run at for 30 min. Near-infrared spectroscopy-derived microvascular responsiveness was preserved with the PS group [(pre: 0.53 ± 0.009%/s) (post: 0.56 ± 0.012%/s; P = 0.55)]. However, there was a significant reduction in the sham control group [(pre: 0.67 ± 0.010%/s) (post: 0.51 ± 0.007%/s; P = 0.05)] after treadmill exercise. Flow-mediated vasodilation (FMD) of the popliteal artery showed similar responses. In the PS group, FMD [(pre: 7.23 ± 0.74%) (post: 5.86 ± 1.01%; P = 0.27)] did not significantly decline after exercise. In the sham control group, FMD [(pre: 8.69 ± 0.72%) (post: 5.24 ± 1.24%; P < 0.001)] was significantly reduced after treadmill exercise. Vascular function may be more resilient if intermittent PS is performed before moderate-intensity exercise and, importantly, can be performed by most individuals.NEW & NOTEWORTHY We demonstrate for the first time that popliteal artery and gastrocnemius microvascular responsiveness after acute aerobic exercise are reduced. The decline in vascular function was mitigated in those who performed intermittent passive stretching before the exercise bouts. Collectively, these findings suggest that intermittent passive stretching is a novel method to increase vascular resiliency before aerobic activity.

Endothelial FoxM1 reactivates aging-impaired endothelial regeneration for vascular repair and resolution of inflammatory lung injury.

Aging is a major risk factor of high incidence and increased mortality of acute respiratory distress syndrome (ARDS). Here, we demonstrated that persistent lung injury and high mortality in aged mice after sepsis challenge were attributable to impaired endothelial regeneration and vascular repair. Genetic lineage tracing study showed that endothelial regeneration after sepsis-induced vascular injury was mediated by lung resident endothelial proliferation in young adult mice, whereas this intrinsic regenerative program was impaired in aged mice. Expression of forkhead box M1 (FoxM1), an important mediator of endothelial regeneration in young mice, was not induced in lungs of aged mice. Transgenic FOXM1 expression or in vivo endothelium-targeted nanoparticle delivery of the FOXM1 gene driven by an endothelial cell (EC)-specific promoter reactivated endothelial regeneration, normalized vascular repair and resolution of inflammation, and promoted survival in aged mice after sepsis challenge. In addition, treatment with the FDA-approved DNA demethylating agent decitabine was sufficient to reactivate FoxM1-dependent endothelial regeneration in aged mice, reverse aging-impaired resolution of inflammatory injury, and promote survival. Mechanistically, aging-induced Foxm1 promoter hypermethylation in mice, which could be inhibited by decitabine treatment, inhibited Foxm1 induction after sepsis challenge. In COVID-19 lung autopsy samples, FOXM1 was not induced in vascular ECs of elderly patients in their 80s, in contrast with middle-aged patients (aged 50 to 60 years). Thus, reactivation of FoxM1-mediated endothelial regeneration and vascular repair may represent a potential therapy for elderly patients with ARDS.

Effects of dipeptidyl peptidase 4 inhibition on the endothelial control of the vascular tone.

Dipeptidyl peptidase 4 (DPP4) is a serine protease known to cleave incretin hormones, which stimulate insulin secretion after food intake, a fact that supported the development of its inhibitors (DPP4i or gliptins) for the treatment of type 2 diabetes mellitus. In addition to their glucose-lowering effects, DPP4i show benefits for the cardiovascular system that could be related, at least in part, to their protective action on vascular endothelium. DPP4i have been associated with the reversal of endothelial dysfunction, an important predictor of cardiovascular events and a hallmark of diseases such as atherosclerosis, diabetes mellitus, hypertension, and heart failure. In animal models of these diseases, DPP4i increase nitric oxide bioavailability and limits oxidative stress, thereby improving the endothelium-dependent relaxation. Similar effects on flow-mediated dilation and attenuation of endothelial dysfunction have also been noted in human studies, suggesting a value for gliptins in the clinical scenario, despite the variability of the results regarding the DPP4i used, treatment duration, and presence of comorbidities. In this mini-review, we discuss the advances in our comprehension of the DPP4i effects on endothelial regulation of vascular tone. Understanding the role of DPP4 and its involvement in the signaling mechanisms leading to endothelial dysfunction will pave the way for a broader use of DPP4i in conditions that endothelial dysfunction is a pivotal pathophysiological player.

Impact of unilateral dual-brachial arteries on endothelial-dependent and endothelial-independent vasodilation: a case study.

TAKE HOME MESSAGE: Our case study indicated that a bifurcated brachial artery exhibited worse vasodilatory responses relative to an intact contralateral artery.

Preserved endothelium-independent vascular function with aging in men and women: evidence from the peripheral and cerebral vasculature.

In the peripheral and cerebral vasculature, the impact of aging and sex on the endothelial-independent functional capacity of vascular smooth muscle cells (VSMCs) is not well understood, nor is it known whether such VSMC functions in these vascular beds reflect one another. Therefore, endothelium-independent dilation, at both the conduit (Δ diameter) and microvascular (Δ vascular conductance, VC) level, elicited by sublingual nitroglycerin (NTG, 0.8 mg of Nitrostat), compared with sham-delivery (control), was assessed using Doppler ultrasound in the popliteal (PA) and middle cerebral (MCA) artery of 20 young [23 ± 4 yr, 10 males (YM)/10 females (YF)] and 21 old [69 ± 5 yr, 11 males (OM)/10 females (OF)] relatively healthy adults. In the PA, compared with zero, NTG significantly increased diameter in all groups (YM: 0.29 ± 0.13, YF: 0.35 ± 0.26, OM: 0.30 ± 0.18, OF: 0.31 ± 0.14 mm), while control did not. The increase in VC only achieved significance in the OF (0.22 ± 0.31 mL/min/mmHg). In the MCA, compared with zero, NTG significantly increased diameter and VC in all groups (YM: 0.89 ± 0.30, 1.06 ± 1.28; YF: 0.97 ± 0.31, 1.84 ± 1.07; OM: 0.90 ± 0.42, 0.72 ± 0.99; OF: 0.74 ± 0.32, 1.19 ± 1.18, mm and mL/min/mmHg, respectively), while control did not. There were no age or sex differences or age-by-sex interactions for both the NTG-induced PA and MCA dilation and VC. In addition, PA and MCA dilation and VC responses to NTG were not related when grouped by age, sex, or as all subjects (r = 0.04-0.44, P > 0.05). Thus, peripheral and cerebral endothelial-independent VSMC function appears to be unaffected by age or sex, and variations in such VSMC function in one of these vascular beds are not reflected in the other.NEW & NOTEWORTHY To confidently explain peripheral and cerebral vascular dysfunction, it is essential to have a clear understanding of the endothelial-independent function of VSMCs across age and sex. By assessing endothelium-independent dilation using sublingual nitroglycerin, endothelial-independent VSMC function in the periphery (popliteal artery), and in the cerebral circulation (middle cerebral artery), was not different due to age or sex. In addition, endothelial-independent VSMC function in one of these vascular beds is not reflected in the other.

No acute hyperglycemia induced impairment in brachial artery flow-mediated dilation before or after aerobic exercise training in young recreationally active males.

There is some evidence that transient endothelial dysfunction induced by acute hyperglycemia may be attenuated by a single bout of aerobic exercise. However, the impact of aerobic exercise training on acute hyperglycemia-induced endothelial dysfunction has not been explored. The purpose of this study was to determine the impact of aerobic exercise training on the endothelial function response to acute hyperglycemia. Brachial artery flow-mediated dilation (FMD) was assessed in 24 healthy males (21 ± 1 years) pre-, 60 and 90 min post ingestion of 75 g of glucose. Participants completed a four-week control (CON; n = 13) or exercise training (EX; n = 11) intervention. The EX group completed four weeks of cycling exercise (30 min, 4×/week at 65% work rate peak). Cardiorespiratory fitness ([Formula: see text]O2peak) increased and resting HR decreased in EX, but not CON post-intervention (p < 0.001). Glucose and insulin increased (p < 0.001) following glucose ingestion, with no significant difference pre- and post-intervention. In contrast to previous research, FMD was unaffected by glucose-ingestion, pre- and post-intervention in both groups. In conclusion, acute hyperglycemia did not impair endothelial function, before or after exercise training. Relatively high baseline fitness ([Formula: see text]O2peak ~ 46 mL/kg/min) and young age may have contributed to the lack of impairment observed. Further research is needed to examine the impact of exercise training on hyperglycemia-induced impairments in endothelial function in sedentary males and females.