bluuebunny/crossref_metadata_2025_split huggingface dataset:
N‐cadherin strengthens VE‐cadherin adhesion through Trio/Rac1 signaling
Authors: Kruse Kevin Jonathan , Huang Fei , Sun Ying , Vogel Steve , Malik Asrar , Komarova Yulia 
Published: November 2023

The vascular endothelium is comprised of a monolayer of endothelial cells (ECs) lining the blood vessels, which functions as a semi‐permeable barrier between blood and the surrounding tissue. Vascular Endothelial (VE)‐cadherin, which forms homotypic adhesions between ECs at adherens junctions (AJs), is the main adhesive molecule that restricts the passage of protein rich fluids across the endothelial monolayer. Along with VE‐cadherin, ECs express Neural (N)‐cadherin, which is excluded from AJs but forms heterotypic adhesions between ECs and mural cells at the abluminal surface of the endothelium. While the role of VE‐cadherin adhesion in regulating endothelial barrier function has been well established, the role of N‐cadherin in ECs remains mainly unknown. We have demonstrated that inducible deletion of Cdh2 gene (encoding N‐cadherin in endothelial cells of adult mice) results in increased permeability of the endothelial vessel wall to albumin in the lung, brain, and kidney. Consistent with these results, accumulation of VE‐cadherin at AJs in endothelial cells of N‐cadherin EC‐KO mice in vivo was significantly reduced. To investigate N‐cadherin adhesion‐mediated signaling in endothelial monolayers, we covalently attached the extracellular domain of N‐cadherin to an Ni‐NTA surface in an oriented manner. N‐cadherin adhesion‐mediated signaling promoted recruitment of VE‐cadherin to AJs. Depletion of N‐cadherin in endothelial cells abolished this effect, suggesting that N‐cadherin adhesion‐mediated signaling promotes assembly of VE‐cadherin adhesion. Using a combination of N‐cadherin coated biomimetic platforms with mass spectroscopy, we isolated and analyzed N‐cadherin complexes. We found that a Rac1 activator, Trio, is recruited to N‐cadherin complexes to activate Rac1 signaling at AJs. This was consistent with formation of lamellipodia protrusions above AJs and increased Rac1 activity as determined by a Rac1 FRET biosensor. Depletion of Trio decreased recruitment of VE‐cadherin to AJs and resulted in a loss of Rac1 activity downstream of N‐cadherin adhesion. These data cumulatively demonstrate that N‐cadherin promotes assembly of VE‐cadherin adhesion through Trio/Rac1 signaling.Support or Funding InformationNIH R01 HL103922AHA 16PRE27260230
Physical training improves cardiac structure and function, antioxidant capacity, and exercise tolerance in spontaneously hypertensive rats
Authors: Okoshi Marina Politi , Pagan Luana , Damatto Ricardo , Cezar Marcelo , Campos Dijon , Lima Aline , Damatto Felipe , Gomes Mariana , Caldonazo Tulio , Okoshi Katashi 
Published: November 2023

IntroductionChronic hemodynamic overload such as hypertension induces genetic, molecular, cellular, and interstitial alterations which clinically manifest as changes in heart size, shape, and function, a process known as cardiac remodeling. Pressure overload caused by hypertension may produce imbalance between reactive oxygen species (ROS) production and antioxidant capacity. Exercise plays an important role in mitigating cardiovascular risk factors such as hypertension. The aim of this study was to evaluate the influence of physical training on cardiac structures and function, physical capacity, and myocardial oxidative stress in spontaneously hypertensive rats (SHR).MethodsThirteen month old SHR were divided into two groups: sedentary (SED, n=18) and exercised (EX, n=22). Physical training was performed 5 times per week for 16 weeks on a treadmill. Physical performance was assessed by exercise test on a treadmill with a gradual speed increase. Systolic arterial pressure (SAP) was measured by tail cuff method. Echocardiogram (Echo) was performed to evaluate in vivo cardiac structures and left ventricular (LV) function. In vitro myocardial function was analyzed in LV papillary muscle preparations. Cardiomyocyte size was measured in LV histological sections. Myocardial antioxidant enzyme activity was quantified by spectrophotometry. NADPH oxidase activity was analyzed by the lucigenin reduction method. Statistics: Student's t test (p<0.05).ResultsPhysical capacity was higher in EX. SAP did not differ between groups at the end of the experiment (SED 194 ± 22 vs. EX 188 ± 12 mmHg). Echo showed reduced diastolic posterior wall thickness (SED 1.63 ± 0.10 vs. EX 1.53 ± 0.08 mm), left atrium diameter (SED 6.57 ± 0.51 vs. EX 6.18 ± 0.49 mm), left atrium diameter‐to‐aorta diameter ratio (SED 1.49 ± 0.11 vs. EX 1.42 ± 0.13), and LV relative wall thickness (SED 0.43 ± 0.05 vs. EX 0.40 ± 0.04) in EX group. The in vitro myocardial functional study showed better performance in EX (positive derivative of tension developed: SED 52.2 ± 12.4 vs. EX 63.4 ± 9.49 g/mm2/s). Cardiomyocyte size and NADPH oxidase activity did not differ between groups. Antioxidant enzymes superoxide dismutase and catalase activity was higher in EX.ConclusionPhysical training improves exercise capacity and induces beneficial effects on cardiac structures and function and myocardial antioxidant capacity in spontaneously hypertensive rats.Support or Funding InformationSupport: FAPESP, CNPq, and CAPES
Heart Rate Recovery Improvement Is Greater After Evening Than Morning Aerobic Training In Treated Hypertensive Men
Authors: de Brito Leandro Campos , Peçanha Tiago , Fecchio Rafael , Rezende Rafael , Sousa Patricia , Silva Giovânio , Abreu Andrea , de Mion Decio Campos , Halliwill John , Forjaz Claudia 
Published: November 2023

IntroductionIn hypertensive individuals, aerobic training improves heart rate recovery (HRR), which reflects an improvement on cardiovascular autonomic regulation. However, autonomic function is influenced by time of day, being possible to suppose that training at different times of day might promote different autonomic adaptations, which need to be investigated.ObjectiveTo compare the effect of aerobic training performed in the morning and in the evening on HRR indexes of hypertensive men.MethodsForty treated hypertensive men were allocated into four groups: morning control (MC, n=9); morning training (MT, n=12); evening control (EC, n=9); evening training (ET, n=10). Training groups performed cycle ergometer exercise 3 times/week for 45 min at an intensity that progressed from the heart rate (HR) at anaerobic threshold to the HR 10% below the respiratory compensation point. Control groups performed stretching exercise 3 times/week for 30 min. At the beginning of the study and after 10 weeks, all subjects underwent, two maximal exercise tests, in a random order: one conducted in the morning (7 – 9 a.m.) and another in the evening (8 – 10 p.m.). T30 (short‐term time‐constant of HRR – parasympathetic reactivation marker) and HRR300s (HR reduction at 300 s of recovery – sympathetic withdrawal marker) were measured. A 2‐way ANOVA for repeated measures was employed at each time of day assessment, considering the main factors: group (MC, MT, EC, ET) and condition (before vs after the intervention), p≤ 0.05.ResultsFor evening assessment, T30 did not change for any group, HR300s did not change in the control groups (MC and EC), but improved significantly in the training groups and this improvement was greater in the ET than MT (MT −45±11 vs. −49±10 bpm and ET −45±13 vs. −53±10 bpm, p<0.04). For morning assessment, there were no changes for either T30 or HRR300s, in any group.ConclusionAerobic training improves sympathetic withdrawal after a maximal exercise test performed in the evening, and this adaptation is more evident when training is performed in the evening.Support or Funding InformationFinancial support: FAPESP: 2014/21667‐6. FAPESP: 2016/19090‐8.
Regulation of Autophagy during Chronic Contractile Activity‐Induced Muscle Adaptations
Authors: Kim Yuho , Triolo Matthew , Hood David A 
Published: November 2023

Autophagy is integral in the remodeling of skeletal muscle in response to various stimuli such as energy status, exercise, and/or other cellular stress. However, it currently remains obscure how autophagy is regulated in skeletal muscle over the course of training adaptations. In this study, we examined autophagic regulation in skeletal muscle of rats exposed to chronic contractile activity (CCA; 6 hours/day, 9V, 10 Hz continuous, 0.1 ms pulse duration) for 1, 3, and 7 days (N=8/each group). CCA resulted in muscle mitochondrial adaptation by day 7, as shown by the increase in PGC‐1α, a master regulator of mitochondrial biogenesis. This was supported by significant increases in other mitochondrial markers such as COX‐I and COX‐IV protein levels, as well as COX activity. Notably, the ratio of LC3 II/LC3 I, an indicator of autophagy, decreased by day 7 largely due to a significant increase in LC3 I. Furthermore, autophagic induction marker p62 appeared to be elevated on day 3 and returned to basal levels by day 7. We found that the lysosomal system is concomitantly upregulated in response to training whereby TFEB, a primary regulator of lysosomal biogenesis, increased 2‐fold by day 7 along with other lysosomal markers including LAMP1, LAMP2A, and MCOLN1. Our findings suggest that, in response to chronic exercise, autophagy is upregulated prior to mitochondrial adaptations, and the lysosomal system may play an important role in mediating autophagy and mitochondrial turnover in skeletal muscle during adaptations to a higher mitochondrial content.Support or Funding InformationThis work is supprted by Natural Sciences and Engineering Research Council of Canada (NSERC).
Physiological cardiac hypertrophy of exercise training is absent in mice deficient in adiponectin
Authors: Muller‐Delp Judy Marie , Dieseldorf‐Jones Karissa Marie , Pinto Jose Marie , Burodonovich Kyle , Hotta Kazuki , Delp Michael , Behnke Bradley 
Published: November 2023

Adiponectin is known to exert protective effects in the post‐ischemic myocardium; however, its role in physiological cardiac hypertrophy induced by exercise training remains unknown. We tested the hypothesis that adiponectin is necessary in exercise training‐induced physiological cardiac hypertrophy. Adult C57BL/6 wild‐type (WT) or homozygous adiponectin knockout (AdipoKO) mice were obtained at 10 wks of age and underwent treadmill exercise training (12 m/min, 5° incline, 1 hr/day, 5 days/wk for 8 wks) or remained sedentary in cages. At the beginning and end of the exercise training or cage confinement period, echocardiographic assessment of cardiac function was performed with the Vevo 2100 high‐resolution imaging system. M‐mode imaging was used to evaluate systolic and diastolic dimensions, posterior and anterior wall thickness, fractional shortening and ejection fraction. Pulsed‐wave doppler was used to measure early (E wave) and late (A wave) mitral valve inflow, and to calculate isovolumic relaxation time. In WT mice, exercise training increased left ventricular (LV) mass, and anterior and posterior wall thickness, without a change in chamber diameter. End‐systolic volume decreased with exercise training, contributing to increased ejection fraction. Fractional shortening also increased with exercise training in WT mice. In contrast, in WT and KO sedentary mice, LV mass and anterior and posterior wall thickness did not change over the 8‐wk period. In sedentary WT mice, chamber diameter did not change, but in sedentary Adipo KO mice, chamber diameter increased over 8 wks. In Adipo KO mice, 8 weeks of exercise training did not produce the adaptations that occurred in WT mice. As in sedentary KO mice, LV mass and anterior and posterior wall thickness did not change over the 8‐wk period of training. Ejection fraction and fractional shortening decreased and end‐systolic volume increased during the 8‐wk training period in Adipo Ko mice. Similar to sedentary Adipo KO mice, chamber diameter increased in exercise trained Adipo KO mice. These data indicate that the outward hypertrophy and increased systolic function that occurs with exercise training in young adult mice is absent in age‐matched adiponectin‐deficient mice. Thus, these results suggest that adiponectin is required for the physiological hypertrophy that is induced by exercise training in the healthy, adult heart.Support or Funding InformationNIH R21 AG044858
Effects of Hybrid Exercise Program on Subclinical Vascular Markers in Young Patients with Permanent Lower‐Limb Disability
Authors: Suksom Daroonwan , Srihirun Kanang , Siripatt Apanchanit , Siripanya Saowalak , Tanaka Hirofumi 
Published: November 2023

Patients with permanent lower limb disability rely on wheel chair for transportation and daily activities. These patients suffer from a lack of physical activity and experience markedly elevated risks of cardiometabolic diseases. In the present study, we investigated the effects of hybrid upper body exercise program on physical fitness and vascular functions in young patients with permanent lower limb disability. Twenty nine males and females with permanent lower limb disability aged 26.0±1.4 years were randomly assigned into the sedentary time control (CON; n=15) and the exercise training (ET; n=14) groups. The supervised exercise training program consisted of a variety of upper limb exercises, including stretching exercises, moderate intensity aerobic exercise incorporating elements of Muay Thai and resistance exercise with rubber strings for 40 min/day, 3 days/wk, for 12 weeks. Before and after the exercise interventions, physical fitness and blood biochemistry were assessed in all participants. A variety of vascular functions including arterial wall thickness, carotid intima‐media thickness (IMT), vascular reactivity, flow‐mediated dilatation (FMD), and brachial‐ankle pulse wave velocity (baPWV), an index of arterial stiffness, were measured noninvasively. At baseline, two groups were not different in anthropometric and vascular functional measures. After 12 wks, there were no significant changes in body fat, heart rate at rest, and systolic blood pressure in both groups. Diastolic blood pressure decreased significantly (p<0.05) only in the ET group. Forearm muscle strength increased significantly (p<0.05) in both CON and ET groups. The ET group experienced greater increases in flexibility and maximal oxygen consumption than the CON group (all p<0.05). IMT and baPWV did not change significantly in both groups. FMD increased significantly (p<0.05) only in the ET group. These results indicate that aerobic exercise training combined with resistance exercise training program had beneficial effects in improving flexibility, cardiovascular fitness, and macrovascular functions in patients with permanent lower limb disability.Support or Funding InformationSupported by Physical Activities Research Center, Thai Health Promotion Foundation.
Sympathetic Nervous System Activation Reduces Contraction‐induced Rapid Vasodilation in the Leg of Humans Independent of Age
Authors: Hughes William E , Kruse Nicholas T , Casey Darren P 
Published: November 2023

Aging is associated with attenuated vasodilation and hyperemia following a single skeletal muscle contraction in both the arm and leg. We previously demonstrated that enhanced sympathetic vasoconstrictor tone contributes to the blunted skeletal muscle contraction‐induced rapid onset vasodilation (ROV) in the forearm of older adults. However, evidence suggests that limb‐specific differences in the regulation of vascular tone exist with aging. Therefore, we sought to examine whether elevated sympathetic tone in the leg contributes to the age‐related reductions in contraction‐induced ROV. Healthy, young (n=13; 24±1yr; 7M/6F) and older (n=10; 67±1yr; 6M/4F) adults performed single muscle contractions in the right leg [20% and 40% work rate maximum (WRmax)] under control (no sympathetic stimulus) and enhanced sympathetic nervous system activity (via a cold pressor test; CPT) conditions. CPT testing consisted of placing the left foot in an ice‐water bath (4° C) for 4 minutes. Femoral artery diameter and mean blood velocity were measured using Doppler ultrasound. Leg vascular conductance (VC; ml· min−1· 100mmHg−1) was calculated using blood flow (mL· min−1) and mean arterial pressure (mmHg). Under control conditions, peak (ΔVC from baseline) and total (area under the curve over 30 cardiac cycles post contraction) vasodilator responses were attenuated in older adults across exercise intensities (P<0.05). Increased sympathetic vasoconstrictor tone via CPT reduced peak and total VC responses in both young and older adults across exercise intensities (P<0.05). The magnitude (%) of reduction did not differ between young vs. older adults for peak (20% WRmax: −25±5% vs. −22±4%, P=0.57 and 40% WRmax: −21±6% vs. −29±6%, P=0.37) or total VC (20% WRmax: −28±5% vs. −37±7%, P=0.29 and 40% WRmax: −22±8% vs. −35±7%, P=0.20). Due to differences in WRmax between age groups, comparisons in the ROV response were also made in a subset of subjects (9 young/8 older) matched for an approximate absolute workload (~10W). Workload matched responses revealed that age‐associated reductions in peak ΔVC and total VC under control conditions still persisted (P<0.05). Moreover, there were no differences in the magnitude of reduction in peak (−20±7% vs. −24±5%, P=0.34) or total VC (−22±8% vs. −29±4%, P=0.23) between young vs. older adults during the CPT trials. Our data demonstrate that 1) independent of age, sympathetic stimulation via CPT reduces parameters of ROV in the leg; and 2) the substantial reductions in leg ROV with aging does not appear to be explained by elevated sympathetic vasoconstrictor tone.Support or Funding InformationFunded by NIH HL‐105467 (DPC)
Combined Effect of Heating and Electrical Stimulation on Endothelial Vasodilator Function
Authors: Iwamoto Erika , Oiwa Shotaro , Takami Jiro , Nagaoka Ryohei , Ito Shota , Neki Toru , Katayose Masaki 
Published: November 2023

Endothelial dysfunction contributes to the progression of atherosclerotic disease. Recent studies suggest electrical stimulation (ES) has a beneficial effect on endothelial function. Additionally, local heating also enhances endothelial function via an increase in skin blood flow and shear stress. Interestingly, ES alone can lead to a small increase in skin blood flow, whereas the combination of ES and local heating could generate a synergistic effect on skin blood flow. Therefore, the aim of this study was to test the hypothesis that combined local heating and ES provide the additive improvement on endothelial function than heating and ES alone. On three separate visits, brachial artery flow‐mediated dilation (FMD), an index of endothelium‐dependent vasodilator function, was assessed before and immediately after 30‐min of exposure to electrical stimulation (ES), heating (Heat), or combined electrical stimulation and heating (ES+Heat) in seven young male subjects (Age; 22.3±1.8 years, BMI; 22.1±0.6 kg/m2, Mean±SE). ES was delivered by an electrical stimulator and surface electrodes (5×5cm) placed bilaterally over the right brachioradialis and extensor carpi ulnaris muscles. Heat was performed using a heating pad (42–43□) wrapped around the right forearm. Brachial blood flow and shear rate and forearm skin blood flow were measured throughout each intervention. Skin blood flow at 30 min was increased (% change from baseline) with Heat (300±64%, p=0.001) and ES+Heat (345±69%, p<0.001), but not ES alone (98±20%, p=0.182). Brachial shear rate at 30 min of ES+Heat was higher than that in Heat (ES+Heat vs. Heat. 168±13 vs. 101±14 sec−1, p=0.026). However, brachial shear rate in ES+Heat vs. ES alone did not differ (168±13 vs. 122±16 sec−1, p=0.162). Importantly, ES+Heat induced a significant increase in FMD after the intervention (Pre vs. Post. 4.5±0.4 vs. 6.7±0.7%, p=0.042), whereas FMD did not change with Heat alone (5.2±0.3% vs. 6.1±0.6%, p=0.342) and ES alone (4.8±0.4 vs. 5.0±0.8%, p=0.804). These results demonstrated that combined heating and electrical stimulation could be an effective method to increase endothelial vasodilator function.Support or Funding InformationThis study was supported in part by Grant‐in‐Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports, and Culture (Grant No. 25750208, 16K16432)
Effects of Aerobic Capacity on Arterial Stiffness in Individuals with Multiple Sclerosis
Authors: Grigoriadis Georgios , Rosenberg Alexander J. , Wee Sang Ouk , Schroeder Elizabeth C. , Hilgenkamp Thessa I.M. , Griffith Garett , Baynard Tracy 
Published: November 2023

INTRODUCTIONIndividuals with Multiple Sclerosis (MS) exhibit a greater risk of cardiovascular disease than individuals without MS, and increased arterial stiffness is one possible risk factor. Higher aerobic capacity has been associated with lower arterial stiffness in healthy individuals and helps explain lower risk profiles. Individuals with MS in general have low aerobic capacities and the effect of MS may abolish expected relationships between fitness and arterial stiffness.PURPOSETo determine the relationship between peak oxygen consumption (VO2peak) and carotid arterial stiffness in individuals with MS.METHODSThirteen individuals with MS (43 ± 9 yrs; 25.0 ± 3.7 kg/m2) underwent an individualized incremental treadmill test to volitional exhaustion with measures of oxygen uptake. Carotid arterial stiffness was measured by ultrasonography prior to the treadmill test, and echo‐tracking software was used to calculate the β‐stiffness index, pressure‐strain elasticity modulus (Ep) and arterial compliance (AC). Bivariate correlations were implemented to examine the linear relationship between VO2peak and carotid arterial stiffness. Partial correlations were performed to control for body weight.RESULTSNegative correlations were observed between absolute VO2peak and β‐stiffness index, (p<0.05) and Ep (p<0.05), whereas a positive correlation was found with AC (p<0.05). However, the significance between VO2peak and carotid stiffness variables was eliminated when controlling for body weight.CONCLUSIONThe findings suggest that aerobic capacity is negatively associated with carotid arterial stiffness and positively associated with arterial compliance, while body weight influences these relationships in an expected manner. Thus, aerobic training and/or weight loss might be an effective treatment to decrease arterial stiffness and consequently risk of cardiovascular disease in a population with MS.

Arterial Stiffness Variables
Absolute VO2peak Bivariate Correlation
Absolute VO2peak Partial Correlation

β‐stiffness index
−0.604*
−0.421

Ep (kPa)
−0.682*
−0.529

AC (mm22/kPa)
0.672*
0.508

Significant correlation: p<0.05