Combined cardiovascular effects of ovariectomy and high-intensity interval training in female spontaneously hypertensive rats.

Hypertensive postmenopausal women are more likely to develop adverse cardiac remodeling and respond less effectively to drug treatment than men. High-intensity interval exercise (HIIE) is a nonpharmacological strategy for the treatment of hypertension; however, the effectiveness in women remains uncertain. This study was designed to evaluate 1) the effects of HIIE training upon morphological and functional markers of cardiovascular health in female SHR and 2) to determine whether the hormonal shift induced by ovariectomy could influence cardiovascular responses to HIIE. Thirty-six SHR were randomly assigned to four groups: ovariectomized sedentary, ovariectomized trained, sham-operated sedentary, and sham-operated trained. The trained rats performed HIIE 5 days/wk for 8 wk. Blood pressure and echocardiographic measurements were performed before and after training in animals. Cardiac response to ß-adrenergic stimulation and the expression of calcium regulatory proteins and estrogen receptors in heart samples were assessed. Endothelium-dependent vasorelaxation in response to acetylcholine was evaluated in aortic rings as well as the expression of nitric oxide synthase isoforms (eNOS and P-eNOS) by Western blotting. In both groups of trained SHR, HIIE induced eccentric cardiac remodeling with greater inotropic and chronotropic effects, as well as an increase in SERCA and ß1AR expression. However, although the trained rats showed improved endothelial function and expression of eNOS and P-eNOS in the aorta, there was no demonstrated effect on blood pressure. In addition, the responses to HIIE training were not affected by ovariectomy. This work highlights the importance of assessing the cardiovascular efficacy and safety of different exercise modalities in women.NEW & NOTEWORTHY This study reports the effects of high-intensity interval exercise (HIIE) training on cardiac and endothelial function in female hypertensive rats. Despite a lack of effect on blood pressure (BP), HIIE training induces eccentric cardiac remodeling with greater functionals effects. Furthermore, training has beneficial effects on endothelial function. However, ovarian hormones do not seem to modulate cardiac and aortic adaptations to this training modality. All this underlines the need to consider training modalities on the cardiovascular system in women.

The role of T-type calcium channels in elderly human vascular function: A pilot randomized controlled trial.

Endothelial dysfunction develops with age and may precede cardiovascular disease. Animal data suggest that T-type calcium channels play an important role in endothelial function, but data from humans are lacking. This study included 15 healthy, sedentary, elderly males for a double blinded, randomized controlled trial. For 8 weeks, they were given 40 mg/day of either efonidipine (L- and T-type calcium channel blocker (CCB)) or nifedipine (L-type CCB). Vascular function was evaluated by graded femoral arterial infusions of acetylcholine (ACh; endothelium-dependent vasodilator) and sodium nitroprusside (endothelium-independent vasodilator) both with and without co-infusion of N-acetylcysteine (NAC; antioxidant). We measured leg blood flow and mean arterial pressure and calculated leg vascular conductance to evaluate the leg vascular responses. Despite no significant change in blood pressure in either group, we observed higher leg blood flow responses (Δ 0.43 ± 0.45 l/min, P = 0.006) and leg vascular conductance (Δ 5.38 ± 5.67 ml/min/mmHg, P = 0.005) to intra-arterial ACh after efonidipine, whereas there was no change in the nifedipine group, and no differences between groups. We found no upregulation of endothelial nitric oxide synthase in vastus lateralis muscle biopsies within or between groups. Smooth muscle cell responsiveness was unaltered by efonidipine or nifedipine. Intravenous co-infusion of NAC did not affect endothelium-dependent vasodilatation in either of the CCB groups. These results suggest that 8 weeks' inhibition of T- and L-type calcium channels augments endothelium-dependent vasodilatory function in healthy elderly males. Further studies are required to elucidate if T-type calcium channel inhibition can counteract endothelial dysfunction.

Evidence of premature vascular dysfunction in young adults who regularly use e-cigarettes and the impact of usage length.

BACKGROUND: Electronic (e-) cigarettes are increasingly popular tobacco products on the US market. Traditional tobacco products are known to cause vascular dysfunction, one of the earliest indicators of cardiovascular disease (CVD) development. However, little is known about the effect of regular e-cigarette use on vascular function. The purpose of this study was to investigate the impact of regular e-cigarette use on vascular function and cardiovascular health in young, healthy adults. METHODS: Twenty-one regular users of e-cigarettes (ECU) and twenty-one demographically matched non-users (NU) completed this study. Vascular health was assessed in the cutaneous microcirculation through different reactivity tests to evaluate overall functionality, endothelium-dependent vasodilation (EDD), and endothelium-independent vasodilation (EID). Macrovascular function was assessed using flow-mediated dilation (FMD). RESULTS: Our results suggest that regular users of e-cigarettes present with premature microvascular impairment when compared to non-users. Specifically, they exhibit lower hyperemic (p = 0.003), thermal (p = 0.010), and EDD (p = 0.004) responses. No differences in EID between the groups were identified. We also identified that individuals who use e-cigarettes for longer than 3 years also present with systemic manifestations, as observed by significantly reduced macrovascular (p = 0.002) and microvascular (p ≤ 0.044) function. CONCLUSIONS: Our novel data suggests that young, apparently healthy, regular users of e-cigarettes present with premature vascular dysfunction in the microcirculation when compared to non-users. We have also identified systemic vascular dysfunction affecting both the micro and macrovasculature in those young individuals who used e-cigarettes for longer than 3 years. Taken together, these findings associate regular e-cigarette use with premature vascular dysfunctions and adverse cardiovascular outcomes.

Elevated blood flow in people with type 1 and type 2 diabetes.

AIMS: The study aimed to evaluate blood flow (BF) and microvascular function in the forearm of people with type 1 and type 2 diabetes at rest and after ischemia. Microvascular function plays a crucial role in regulating BF in peripheral tissues based on metabolic demand. METHODS: People with diabetes and sex-matched healthy controls were recruited. Brachial artery diameter and blood velocity were continuously measured at rest and after ischemia by an automatic tracking system. BF and vascular conductance were then calculated. RESULTS: Forty-nine people with diabetes and 49 controls were enrolled. BF at rest and after ischemia was significantly higher in people with diabetes than controls: Type 1, 243 ± 116 and 631 ± 233 ml/min; controls, 180 ± 106 and 486 ± 227 ml/min; Type 2, 332 ± 149 and 875 ± 293 ml/min; controls 222 ± 106 and 514 ± 224 ml/min. Vascular conductance was significantly higher in Type 2 than in controls at rest and after ischemia. CONCLUSIONS: People with diabetes exhibited significantly increased BF, with Type 2 also showing heightened vascular conductance. Activating metabolic pathways triggered by hyperglycemia may lead to distinct vascular redistribution, potentially impairing blood flow over time. These findings of the study underscore the importance of understanding overall vascular dynamics in diabetes and its implications for vascular health.

The vasoactive effects of bradykinin, vasoactive intestinal peptide, calcitonin gene-related peptide and neuropeptide Y depend on the perivascular tissue in porcine retinal arterioles in vitro.

PURPOSE: The retina contains a number of vasoactive neuropeptides and corresponding receptors, but the role of these neuropeptides for tone regulation of retinal arterioles has not been studied in detail. METHODS: Porcine arterioles with preserved perivascular retinal tissue were mounted in a wire myograph, and the tone was measured after the addition of increasing concentrations of bradykinin, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), substance P (SP), calcitonin gene-related peptide (CGRP) and brain natriuretic peptide (BNP). The experiments were performed during inhibition of the synthesis of nitric oxide (NO), prostaglandins and dopamine and were repeated after removal of the perivascular retinal tissue. RESULTS: Bradykinin, VIP and CGRP induced significant concentration-dependent dilatation and NPY significant concentration-dependent contraction of the arterioles in the presence of perivascular retinal tissue (p < 0.03 for all comparisons) but not on isolated arterioles. BNP and SP had no effect on vascular tone. The NOS inhibitor L-NAME reduced bradykinin- and VIP-induced relaxation (p < 0.001 for both comparisons), whereas none of the other inhibitors influenced the vasoactive effects of the studied neuropeptides. CONCLUSION: The effects of neuropeptides on the tone of retinal arterioles depend on the perivascular retinal tissue and may involve effects other than those mediated by nitric oxide, prostaglandins and adrenergic compounds. Investigation of the mechanisms underlying the vasoactive effect of neuropeptides may be important for understanding and treating retinal diseases where disturbances in retinal flow regulation are involved in the disease pathogenesis.

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.

Short-term cocoa bioflavanol supplementation does not improve cold-induced vasodilation in young healthy adults.

PURPOSE: Cold-induced vasodilation (CIVD) is an oscillatory rise in blood flow to glabrous skin that occurs in cold-exposed extremities. Dietary flavanols increase bioavailable nitric oxide, a proposed mediator of CIVD through active vasodilation and/or withdrawal of sympathetic vascular smooth muscle tone. However, no studies have examined the effects of flavanol intake on extremity skin perfusion during cold exposure. We tested the hypothesis that acute and 8-day flavanol supplementation would augment CIVD during single-digit cold water immersion (CWI). METHODS: Eleven healthy adults (24 ± 6 years; 10 M/1F) ingested cocoa flavanols (900 mg/day) or caffeine- and theobromine-matched placebo for 8 days in a double-blind, randomized, crossover design. On Days 1 and 8, CIVD was assessed 2 h post-treatment. Subjects immersed their 3rd finger in warm water (42 °C) for 15 min before CWI (4 °C) for 30 min, during which nail bed and finger pad skin temperature were measured. RESULTS: Flavanol ingestion had no effect on CIVD frequency (Day 1, Flavanol: 3 ± 2 vs. Placebo: 3 ± 2; Day 8, Flavanol: 3 ± 2 vs. Placebo: 3 ± 1) or amplitude (Day 1, Flavanol: 4.3 ± 1.7 vs. Placebo: 4.9 ± 2.6 °C; Day 8, Flavanol: 3.9 ± 1.9 vs. Placebo: 3.9 ± 2.0 °C) in the finger pad following acute or 8-day supplementation (P > 0.05). Furthermore, average, nadir, and apex finger pad temperatures during CWI were not different between treatments on Days 1 or 8 of supplementation (P > 0.05). Similarly, no differences in CIVD parameters were observed in the nail bed following supplementation (P > 0.05). CONCLUSION: These data suggest that cocoa flavanol ingestion does not alter finger CIVD. Clinical Trial Registration Clinicaltrials.gov Identifier: NCT04359082. April 24, 2020.

Sex Differences in Oxidative Stress-Mediated Reductions in Microvascular Endothelial Function in Young Adult e-Cigarette Users.

BACKGROUND: Chronic electronic-cigarette (EC) use is reported to decrease vascular endothelial function. However, the mechanism(s) mediating this reduction remain unclear. In this study, we examined endothelium- and NO-dependent dilation, and the role of oxidative stress in attenuating these responses, in healthy young EC users (n=20, 10 males/10 females) compared with healthy controls (n=20, 10 males/10 females). We hypothesized that EC would have reduced endothelium- and NO-dependent dilation and administration of the superoxide scavenger tempol would increase these responses in EC. We further hypothesized that female EC would have the greatest reductions in endothelium- and NO-dependent dilation. METHODS: We assessed microvascular endothelium-dependent vasodilator function in vivo by measurement of cutaneous vascular conductance (%CVCmax) responses to a standardized local heating protocol in control and 10 µM tempol-treated sites. After full expression of the local heating response, 15 mM NG-nitro-L-arginine methyl ester (NO synthase inhibition) was perfused. RESULTS: EC had significantly reduced endothelium- (73±15 versus 87±9%CVCmax; P<0.001) and NO-dependent (48±17% versus 62±15%; P=0.011) dilation. Tempol perfusion increased endothelium-dependent (84±12%CVCmax P=0.01) and NO-dependent (63±14% P=0.005) dilation in EC but had no effect in healthy control. Within female sex, EC had lower endothelium-dependent (71±13 versus 89±7%CVCmax; P=0.002) and NO-dependent (50±6 versus 69±11%; P=0.005) dilation compared with healthy control, and tempol augmented endothelium-dependent (83±13%CVCmax; P=0.002) and NO-dependent (62±13%; P=0.015) dilation. There were no group or treatment differences within male sex. CONCLUSION: Healthy young adult EC users have reduced microvascular endothelium-dependent and NO-dependent dilation, driven by greater reductions in female EC users, and mediated in part by superoxide.

Methodological challenges in using human umbilical artery as a model for in vitro studies.

NEW FINDINGS: What is the central question of this study? What are the biggest challenges in performing in vitro studies on isolated human umbilical arteries? What is the main finding and its importance? The protocols presented in this study indicate some potential outcomes important for interpretation of the vascular responsivities of human umbilical arteries and could be useful for planning future in vitro studies with human umbilical arteries. ABSTRACT: Human umbilical artery (HUA) preparations are of particular importance for in vitro studies on isolated blood vessels because their sampling is not risky for the patient, and they can provide the closest possible impression of changes related to the uteroplacental circulation during pre-eclampsia. Using organ bath techniques, useful experimental protocols are provided for measuring some pathophysiological phenomena in the vascular responses of HUAs. Several vasoconstrictors (serotonin, prostaglandin F and phenylephrine) and vasodilators (acetylcholine and minoxidil) were seleted for determination of their vasoactivity in HUAs. The role of L-type voltage-operated calcium channels and different types of potassium channels (KATP , BKCa and KV ) were assessed, as was the impact of homocysteine. Serotonin was confirmed to be the most potent vasoconstrictor, while acetylcholine and phenylephrine caused variability in the relaxation and contraction response of HUA, respectively. The observed increase in serotonin-induced contraction and a decrease in minoxidil-induced relaxation in the presence of homocysteine suggested its procontractile effect on HUA preparations. Using selective blockers, it was determined that KATP and KV channels participate in the minoxidil-induced relaxation, while L-type voltage-dependent Ca2+  channels play an important role in the serotonin-induced contraction. The presented protocols reveal some of the methodological challenges related to HUA preparations and indicate potential outcomes in interpreting the vascular effects of the investigated substances, both in physiological conditions and in the homocysteine-induced pre-eclampsia model.

In vivo noninvasive systemic myography of acute systemic vasoactivity in female pregnant mice.

Altered vasoactivity is a major characteristic of cardiovascular and oncological diseases, and many therapies are therefore targeted to the vasculature. Therapeutics which are selective for the diseased vasculature are ideal, but whole-body selectivity of a therapeutic is challenging to assess in practice. Vessel myography is used to determine the functional mechanisms and evaluate pharmacological responses of vascularly-targeted therapeutics. However, myography can only be performed on ex vivo sections of individual arteries. We have developed methods for implementation of spherical-view photoacoustic tomography for non-invasive and in vivo myography. Using photoacoustic tomography, we demonstrate the measurement of acute vascular reactivity in the systemic vasculature and the placenta of female pregnant mice in response to two vasodilators. Photoacoustic tomography simultaneously captures the significant acute vasodilation of major arteries and detects selective vasoactivity of the maternal-fetal vasculature. Photoacoustic tomography has the potential to provide invaluable preclinical information on vascular response that cannot be obtained by other established methods.

Intrapulmonary arterial contraction assay reveals region-specific deregulation of vasoreactivity to lung injuries.

Intrapulmonary arteries located in the proximal lung differ from those in the distal lung in size, cellular composition, and the surrounding microenvironment. However, whether these structural variations lead to region-specific regulation of vasoreactivity in homeostasis and following injury is unknown. Herein, we employ a two-step method of precision-cut lung slice (PCLS) preparation, which maintains almost intact intrapulmonary arteries, to assess contractile and relaxation responses of proximal preacinar arteries (PaAs) and distal intraacinar arteries (IaAs) in mice. We found that PaAs exhibited robust vasoconstriction in response to contractile agonists and significant nitric oxide (NO)-induced vasodilation. In comparison, IaAs were less contractile and displayed a greater relaxation response to NO. Furthermore, in a mouse model of pulmonary arterial hypertension (PAH) induced by chronic exposure to ovalbumin (OVA) allergen and hypoxia (OVA-HX), IaAs demonstrated a reduced vasocontraction despite vascular wall thickening with the emergence of new αSMA+ cells coexpressing markers of pericytes. In contrast, PaAs became hypercontractile and less responsive to NO. The reduction in relaxation of PaAs was associated with decreased expression of protein kinase G, a key component of the NO pathway, following chronic OVA-HX exposure. Taken together, the PCLS prepared using the modified preparation method enables functional evaluation of pulmonary arteries in different anatomical locations and reveals region-specific mechanisms underlying the pathophysiology of PAH in a mouse model.NEW & NOTEWORTHY Utilizing mouse precision-cut lung slices with preserved intrapulmonary vessels, we demonstrated a location-dependent structural and contractile regulation of pulmonary arteries in health and on noxious stimulations. For instance, chronic ovalbumin and hypoxic exposure increased pulmonary arterial pressure (PAH) by remodeling intraacinar arterioles to reduce vascular wall compliance while enhancing vasoconstriction in proximal preacinar arteries. These findings suggest region-specific mechanisms and therapeutic targets for pulmonary vascular diseases such as PAH.

Targeting cytokine-like protein FAM3D lowers blood pressure in hypertension.

Current antihypertensive options still incompletely control blood pressure, suggesting the existence of uncovered pathogenic mechanisms. Here, whether cytokine-like protein family with sequence similarity 3, member D (FAM3D) is involved in hypertension etiology is evaluated. A case-control study exhibits that FAM3D is elevated in patients with hypertension, with a positive association with odds of hypertension. FAM3D deficiency significantly ameliorates angiotensin II (AngII)-induced hypertension in mice. Mechanistically, FAM3D directly causes endothelial nitric oxide synthase (eNOS) uncoupling and impairs endothelium-dependent vasorelaxation, whereas 2,4-diamino-6-hydroxypyrimidine to induce eNOS uncoupling abolishes the protective effect of FAM3D deficiency against AngII-induced hypertension. Furthermore, antagonism of formyl peptide receptor 1 (FPR1) and FPR2 or the suppression of oxidative stress blunts FAM3D-induced eNOS uncoupling. Translationally, targeting endothelial FAM3D by adeno-associated virus or intraperitoneal injection of FAM3D-neutralizing antibodies markedly ameliorates AngII- or deoxycorticosterone acetate (DOCA)-salt-induced hypertension. Conclusively, FAM3D causes eNOS uncoupling through FPR1- and FPR2-mediated oxidative stress, thereby exacerbating the development of hypertension. FAM3D may be a potential therapeutic target for hypertension.

Estrogen receptor subtype mediated anti-inflammation and vasorelaxation via genomic and nongenomic actions in septic mice.

Aim: Sepsis is a life-threatening disease with high mortality worldwide. Septic females have lower severity and mortality than the males, suggesting estrogen exerts a protective action, but nothing is known about the role of vascular endothelial estrogen receptor subtypes in this process. In the present study, we aimed to study the estrogen receptors on mesenteric arterioles in normal and sepsis mice and to elucidate the underlying mechanisms. Methods: Sepsis was induced in mice by intraperitoneal injection of LPS. The changes in the expression and release of the serum and cell supernatant proinflammatory cytokines, including TNF-α, IL-1ß and IL-6, were measured by qPCR and ELISA, and the functions of multiple organs were analyzed. The functional activities of mouse mesenteric arterioles were determined by a Mulvany-style wire myograph. The expression of phospholipase C (PLC) and inositol 1,4,5-trisphosphate receptor (IP3R) in endothelial cells were examined by Western blot and their functions were characterized by cell Ca2+ imaging. Results: Septic female mice had higher survival rate than the male mice, and pretreatment with E2 for 5 days significantly improved the survival rate and inhibited proinflammatory cytokines in septic male mice. E2 ameliorated pulmonary, intestinal, hepatic and renal multiple organ injuries in septic male mice; and ER subtypes inhibited proinflammatory cytokines in endothelial cells via PLC/IP3R/Ca2+ pathway. E2/ER subtypes immediately induced endothelial-derived hyperpolarization (EDH)-mediated vasorelaxation via PLC/IP3R/Ca2+ pathway, which was more impaired in septic male mice. E2/ER subtypes could rescue the impaired acetylcholine (ACh)-induced EDH-mediated vasorelaxation in septic male mice. Conclusions: E2 through ER subtypes mediates anti-inflammation and vasorelaxation via genomic and nongenomic actions in sepsis. Mechanistically, activation of endothelial ER subtypes reduces proinflammatory cytokines and induces EDH-mediated vasorelaxation via PLC/IP3R/Ca2+ pathway, leading to amelioration of sepsis-induced organ injury and survival rate.

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.

Serum, interstitial and sweat ATP in humans exposed to heat stress: Insights into roles of ATP in the heat loss responses.

Hyperthermia increases intravascular adenosine triphosphate (ATP) and is associated with greater hyperthermia-induced cutaneous vasodilation. Hyperthermia may also increase skin interstitial fluid ATP thereby activating cutaneous vascular smooth muscle cells and sweat glands. We evaluated the hypothesis that whole-body heating would increase skin interstitial fluid ATP, and this response would be associated with an increase in cutaneous vasodilation and sweating. Nineteen (8 females) young adults underwent whole-body heating using a water-perfusion suit to increase core temperature by ~1°C during which time cutaneous vascular conductance (CVC, ratio of laser-Doppler blood flow to mean arterial pressure) and sweat rate (ventilated capsule technique) were measured at four forearm skin sites to minimize between-site variations. Dialysate from the skin sites were collected via intradermal microdialysis. Heating increased serum ATP, CVC, and sweat rate (all p ≤ 0.031). However, heating did not modulate dialysate ATP (median, baseline vs. end-heating: 2.38 vs. 2.70 nmol/ml) (p = 0.068), though the effect size was moderate (Cohen's d = 0.566). While the heating-induced increase in CVC was not correlated with changes in serum ATP (r = 0.439, p = 0.060), we observed a negative correlation (rs = -0.555, p = 0.017) between dialysate ATP and CVC. We did not observe a significant correlation between the heating-induced sweating and serum, dialysate, or sweat ATP (rs = 0.091 to -0.322, all p ≥ 0.222). Altogether, we showed that passive heating increases ATP in blood and possibly skin interstitial fluid, with the latter potentially blunting cutaneous vasodilation. However, ATP does not appear to modulate sweating.

The role of HIV as a risk modifier for coronary endothelial function in young adults.

BACKGROUND: People living with HIV have an increased risk of cardiovascular disease (CVD). Although coronary endothelial function (CEF) is an early direct indicator of CVD, only a few studies have been able to interrogate CEF directly. Most studies have examined vascular endothelial function through indirect assessment of brachial flow-mediated dilatation (FMD). However, peripheral arteries are significantly larger and manifest atherogenesis differently from the coronary arteries, and so produce conflicting results. Additionally, none of these studies focused on young adults who acquired HIV perinatally or in early childhood. OBJECTIVE: The present study investigates CEF in a unique population of young adults with lifelong HIV using direct magnetic resonance imaging (MRI) of coronary FMD (corFMD) with an in-house developed MRI-integrated isometric handgrip exercise system with continuous feedback and monitoring mechanisms (fmIHE). METHODS: Young adults who acquired HIV perinatally or in early childhood (n = 23) and group-matched healthy participants (n = 12) completed corFMD-MRI with fmIHE. CorFMD was measured as the coronary cross-sectional area response to the fmIHE. RESULTS: In univariable and multivariable regression analysis, HIV status was a significant risk modifier. CD8+ T-cell count and smoking pack-years and their interaction with HIV status were independently associated with impaired coronary artery response to fmIHE. In people living with HIV, corFMD was significantly inversely correlated with CD8+ T-cells and smoking pack-years. In a multivariable regression analysis adjusted for age and body mass index, CD8+ T-cells and smoking and their interaction with HIV status remained significant independent predictors of coronary endothelial dysfunction. DISCUSSION: In this unique population of young adults, HIV status was a significant risk modifier, and immune activation and smoking were associated with decreased CEF, directly measured from the coronary vascular response to fmIHE. CONCLUSIONS: Management of CVD risk factors such as smoking and developing strategies that target immune activation in people living with HIV are warranted.

INFLUENCE OF OBESITY ON VASCULAR DYSFUNCTION AFTER TRAUMATIC HEMORRHAGE.

ABSTRACT: Background: Obesity increases the risk for morbidity and mortality after trauma. These complications are associated with profound vascular damage. Traumatic hemorrhage acutely attenuates vascular responsiveness, but the impact of obesity on this dysfunction is not known. The local inflammatory response in vascular cells is also unknown. We hypothesized that obesity potentiates trauma-induced vascular inflammation and dysfunction. Methods: Male Sprague-Dawley rats (~250 g) were fed normal chow (NC; 13.5% kcal fat, n = 20) or high-fat (HF; 60% kcal fat, n = 20) diets for 6 to 8 weeks. Under anesthesia, hemorrhage was induced by a mesenteric artery laceration, a Grade V splenic injury, and hypotension (MAP = 30-40 mm Hg) for 30 minutes. Vascular responsiveness was assessed ex vivo in isolated mesenteric arteries prehemorrhage and posthemorrhage. Gene expression for IL-1ß, and IL-6, prooxidant nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), and α-adrenergic receptor were assessed in carotid artery endothelial cells (ECs) and non-ECs (media + adventitia). Results: In NC rats, hemorrhage attenuated norepinephrine-induced vasoconstriction and endothelium-dependent vasodilation to acetylcholine. In HF rats, baseline norepinephrine-induced vasoconstriction was attenuated compared with NC, but vasoconstriction and endothelium-dependent vasodilation did not change prehemorrhage to posthemorrhage. Hemorrhage led to elevated IL-1ß gene expression in ECs and elevated IL1ß, IL-6, NOX2, and α-adrenergic receptor gene expression in the media + adventitia compared with sham. HF rats had greater EC IL-1 ß and NOX2 gene expression compared with NC rats. The hemorrhage-induced elevation of IL-1ß in the media + adventitia was greatest in HF rats. Conclusion: Traumatic hemorrhage attenuates vascular responsiveness and induces vascular inflammation. The attenuated vascular responsiveness after hemorrhage is absent in obese rats, while the elevated vascular inflammation persists. A HF diet amplifies the arterial inflammation after hemorrhage. Altered vascular responsiveness and vascular inflammation may contribute to worse outcomes in obese trauma patients.

Post-exercise endothelial function is not associated with extracellular vesicle release in healthy young males.

Acute exercise can result in temporary decrease in endothelial functions, which may represent a transient period of risk. Numerous mechanisms underpinning these responses included release of extracellular vesicles (EVs) derived from apoptotic or activated endothelial cells and platelets. This study aims to compare the time course of endothelial responses to moderate-intensity continuous exercise (MICE) and high-intensity interval exercise (HIIE) and the associations with EV release. Eighteen young healthy males (age: 22.6 ± 3.7 years, BMI: 25.6 ± 2.5 m2/kg, and VO2peak: 38.6 ± 6.5 mL/kg/min) completed two randomly assigned exercises: HIIE (10 × 1 min-@-90% heart rate reserve (HRR) and 1 min passive recovery) and MICE (30 min-@-70% HRR) on a cycle ergometer. Flow-mediated dilation (FMD) was used to assess endothelial function and blood samples were collected to evaluate endothelial cell-derived EV (CD62E+) and platelet-derived EV (CD41a+), 10, 60, and 120 min before and after exercise. There were similar increases but different time courses (P = 0.017) in FMD (increased 10 min post-HIIE, P < 0.0001 and 60 min post-MICE, P = 0.038). CD62E+ remained unchanged (P = 0.530), whereas overall CD41a+ release was reduced 60 min post-exercise (P = 0.040). FMD was not associated with EV absolute release or change (P > 0.05). Acute exercise resulted in similar improvements, but different time course in FMD following either exercise. Whilst EVs were not associated with FMD, the reduction in platelet-derived EVs may represent a protective mechanism following acute exercise.

Flow-mediated dilation reference values for evaluation of endothelial function and cardiovascular health.

AIMS: Endothelial function is essential for cardiovascular health, and flow-mediated dilation (FMD) is an established technique to measure it. This paper aims to assess FMD values in apparently healthy individuals and provides reference values to facilitate wider clinical use. METHODS AND RESULTS: In 1,579 apparently healthy individuals (aged 18-76), fasted FMD values (data from 44 studies, 6 institutions, 22 operators) were normally distributed and inversely univariately correlated with age, body mass index, glucose, cholesterol, blood pressure, and brachial artery (BA) diameter. Significant multivariate predictors of FMD were age (-0.4%/decade), BMI (0.04%/kg/m2), smoking (-0.7%), and BA diameter (-0.44%/mm) that together explained 19% of the variability independent of operator, institution or ultrasound machine. Individuals in the high FMD tertile (>6.8%) were younger, had smaller BA diameter, lower blood pressure and cholesterol. In individuals with low- and intermediate fatal cardiovascular risk (SCORE), 26% and 53% of individuals, respectively, had FMD values in the low tertile (<5.4%). After adding data from 385 patients with stable coronary artery disease (CAD), ROC analysis (c = 0.841, P < 0.001) showed that FMD of >6.5% excluded CAD (95% sensitivity; 60% specificity) and FMD <3.1% excluded 95% healthy individuals (95% specificity, 31% sensitivity). A meta-analysis and meta-regression of 82 clinical trials (11 countries, n = 3,509) using similar FMD methodology showed that despite considerable heterogeneity (I2 = 0.97) FMD in healthy individuals was on average 6.4% (95%CI: 6.2%, 6.7%) with no significant differences between countries but a significant age-dependent decline (-0.3%/decade, R2 = 0.13). CONCLUSIONS: We provide an age-adapted frame of FMD reference intervals in apparently healthy individuals for use as a biomarker of cardiovascular health. As the degree of vascular endothelial function integrates environmental and genetic factors with classical CV risk factors, FMD may more comprehensively classify individuals with and without standard modifiable cardiovascular risk factors and serve as a target for cardiovascular prevention.

High altitude differentially modulates potassium channel-evoked vasodilatation in pregnant human myometrial arteries.

High-altitude (>2500 m or 8200 ft) residence reduces uterine artery blood flow during pregnancy, contributing to an increased incidence of preeclampsia and intrauterine growth restriction. However, not all pregnancies are affected by the chronic hypoxic conditions of high-altitude residence. K+ channels play important roles in the uterine vascular adaptation to pregnancy, promoting a reduction in myogenic tone and an increase in blood flow. We hypothesized that, in pregnancies with normal fetal growth at high altitude, K+ channel-dependent vasodilatation of myometrial arteries is increased compared to those from healthy pregnant women at a lower altitude (∼1700 m). Using pharmacological modulation of two K+ channels, ATP-sensitive (KATP ) and large-conductance Ca2+ -activated (BKCa ) K+ channels, we assessed the vasodilatation of myometrial arteries from appropriate for gestational age (AGA) pregnancies in women living at high or low altitudes. In addition, we evaluated the localization of these channels in the myometrial arteries using immunofluorescence. Our results showed an endothelium-dependent increase in KATP -dependent vasodilatation in myometrial arteries from high versus low altitude, whereas vasodilatation induced by BKCa activation was reduced in these vessels. Additionally, KATP channel co-localization with endothelial markers was reduced in the high-altitude myometrial arteries, which suggested that the functional increase in KATP activity may be by mechanisms other than regulation of channel localization. These observations highlight an important contribution of K+ channels to the human uterine vascular adaptation to pregnancy at high altitude serving to maintain normal fetal growth under conditions of chronic hypoxia. KEY POINTS: High-altitude (>2500 m or 8200 ft) residence reduces uterine blood flow during pregnancy and fetal growth. Animal models of high altitude/chronic hypoxia suggest that these reductions are partially due to reduced vascular K+. channel responses, such as those elicited by large conductance Ca2+ -activated (BKCa ) and ATP-sensitive (KATP ) K+ channel activation. We found that women residing at high versus low altitude during pregnancy showed diminished myometrial artery vasodilatory responses to endothelium-independent BKCa channel activation but greater responses to endothelium-dependent KATP channel activation. Our observations indicate that KATP channels play an adaptive role in maintaining myometrial artery vasodilator sensitivity under chronic hypoxic conditions during pregnancy. Thus, KATP channels represent potential therapeutic targets for augmenting uteroplacental blood flow and, in turn, preserving fetal growth in cases of uteroplacental hypoperfusion.