bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long Term Endurance Exercise Training Ameliorates Conduit Artery Retrograde and Oscillatory Shear in Older Adults
Authors: Schneider Aaron C. , Ueda Kenichi , Casey Darren P. 
Published: November 2023

With aging, there tends to be an increase in retrograde and oscillatory shear in peripheral conduit arteries of humans. Whether the increase in shear rate is due to the aging process or an effect of a less than active lifestyle that often accompanies aging is unknown. Therefore, in a cross‐sectional study we evaluated whether chronic endurance exercise training attenuates retrograde and oscillatory shear in older adults. Brachial and common femoral artery mean blood velocities and diameter were determined via Doppler ultrasound under resting conditions in 13 young (Y = 24 ± 1 years), 17 older untrained (OU = 66 ± 1 years), and 16 older endurance exercise trained adults (OT = 66 ± 2 years). Mean shear rate (s−1) was defined as 4·Vm/D, where Vm is mean blood velocity (cm · s−1) and D is arterial diameter (cm). For calculations of antegrade and retrograde shear rate, antegrade and retrograde mean blood velocities were used, respectively. Oscillatory shear index is an indicator of the magnitude of oscillation between antegrade and retrograde shear. Vascular resistance in the forearm and leg were also calculated (mean arterial pressure/blood flow) using each respective limb blood flow and mean arterial pressure derived from beat‐to‐beat finger plethysmography measurements. Brachial artery retrograde (−9.1 ± 1.7 vs. −12.6 ± 2.3 s−1; P = 0.35) and oscillatory (0.14 ± 0.02 vs. 0.14 ± 0.02 arbitrary units; P = 0.99) shear were similar between the OT and OU groups, whereas brachial retrograde and oscillatory shear were greater in OU compared to Y adults (−5.0 ± 0.9 s−1, 0.08 ± 0.01 arbitrary units, both P < 0.05; respectively). There was no difference between the Y and OT brachial artery retrograde (P = 0.29) and oscillatory (P = 0.07) shear. Common femoral artery retrograde (−6.3 ± 0.7 s−1) and oscillatory (0.21 ± 0.02 arbitrary units) shear was reduced in OT compared to the OU group (−10.4 ± 1.0 s−1 and 0.30 ± 0.02 arbitrary units, both P < 0.05; respectively), yet similar to Y adults (−7.1 ± 1.0 s−1 and 0.19 ± 0.02 arbitrary units, P = 0.81 and 0.87; respectively). Vascular resistance did not differ between groups in the arm (P = 0.56) or the leg (P = 0.32). However, vascular resistance was inversely related to retrograde shear in the brachial and common femoral artery (r = −0.33 and −0.37, both P < 0.05; respectively) and positively related to oscillatory shear in the brachial and common femoral artery (r = 0.46 and 0.54, both P < 0.05; respectively) when all subjects were pooled together. Our results suggest that chronic endurance exercise training in older adults ameliorates retrograde and oscillatory shear rate patterns, particularly in the common femoral artery.Support or Funding InformationResearch was supported by NIH HL‐105467 (DPC)
Elevated Extracellular Potassium Prior to Muscle Contraction Reduces Exercise Hyperemia in Humans
Authors: Terwoord Janee D. , Hearon Christopher M. , Luckasen Gary J. , Larson Dennis G. , Joyner Michael J. , Dinenno Frank A. 
Published: November 2023

During muscle contractions, an increase in interstitial potassium (K+) and subsequent activation of inwardly‐rectifying K+ (KIR) channels is thought to be a functional vasodilatory signal contributing to exercise hyperemia. Indeed, our laboratory has recently demonstrated that inhibition of KIR channels blunts exercise hyperemia ~30% in humans. In theory, the vasodilatory response to changes in interstitial K+ during muscle contraction could be minimized by artificially elevating the concentration of K+ perfusing the vasculature prior to the onset of muscle contractions, thus limiting further recruitment of this pathway and blunting the dilatory response to exercise. We tested the hypothesis that infusion of potassium chloride (KCl) to elevate extracellular potassium concentrations and induce hyperpolarization prior to the onset of muscle contractions would reduce the contribution of this mechanism to the dilatory response to exercise. In young adults (n = 10), we measured forearm blood flow (FBF; Doppler ultrasound) and calculated changes in vascular conductance (FVC; FBF/intra‐arterial blood pressure) during 4 minutes of rhythmic handgrip exercise at 10% of maximal voluntary contraction during 1) control conditions (CTRL), 2) local, intra‐arterial infusion of KCl to elevate the concentration of K+ prior to the initiation of exercise, and 3) intra‐arterial infusion of sodium nitroprusside (SNP) as a high flow control to match the K+‐induced vasodilation observed at rest. As intended, infusion of KCl or SNP elevated resting FVC similarly prior to the onset of exercise (CTRL: 40 ± 7 vs. KCl: 84 ± 13 and SNP: 85 ± 14 ml·min−1·100 mmHg−1; both P < 0.01 vs. CTRL). Infusion of KCl diminished the subsequent vasodilatory response to handgrip exercise by ~31% when compared to control conditions (ΔFVC: KCl: 92 ± 14 vs. CTRL: 133 ± 16 ml·min−1·100 mmHg−1; P < 0.01), whereas elevation of resting FVC with SNP prior to contractions did not change the vasodilatory response to exercise (ΔFVC, SNP: 117 ± 15 vs. CTRL: 133 ± 16 ml·min−1·100 mmHg−1; P = NS). These findings indicate that K+‐mediated hyperpolarization prior to the onset of muscle contractions blunts the normal vasodilatory response to exercise, which supports a role for elevated K+ signaling in the hyperemic response to exercise in humans.Support or Funding InformationHL119337, HL095573
Hypercapnic Cerebral Vasodilation: Contribution of Cyclooxygenase and Reactive Oxygen Species in Healthy and Metabolic Syndrome Adults
Authors: Harrell John , Peltonen Garret , LaPlante Kaylie , Ernst Brady , Schrage William 
Published: November 2023

Excess reactive oxygen species (ROS) limit cerebral vasodilation in animal models of metabolic syndrome (MetSyn). Cyclooxygenase (COX) may be a source of ROS, but data are lacking in humans. We hypothesized ROS limit hypercapnic cerebral vasodilation in human MetSyn, but COX is not the source. We measured middle cerebral artery velocity (MCAv) with transcranial Doppler ultrasound in 12 MetSyn adults (34±2 yr) and 12 healthy adults (28±1 yr) during baseline and hypercapnia (end‐tidal CO‐2 +10 mmHg). Hypercapnia was performed under three conditions: 1) control, 2) ROS inhibition (intravenous ascorbic acid infusion), and 3) combined ROS and COX inhibition (oral indomethacin). MCAv was normalized for MABP and expressed as cerebrovascular conductance index [CVCi = (MCAv ÷ MABP) * 100]. The change in CVCi from baseline (ΔCVCi) indicated hypercapnic cerebral vasodilation. Hypercapnia increased CVCi in both groups across all conditions (p<0.05). ΔCVCi was similar between groups in control trials and was unaffected by ROS inhibition. Combined ROS‐COX inhibition greatly decreased hypercapnic ΔCVCi (p<0.05) similarly in both groups (healthy: 70±7% vs. MetSyn 84±8%). The decrease in hypercapnic cerebral vasodilation with combined ROS‐COX inhibition was quantitatively greater than previous published results with COX inhibition alone (~50% in both groups). In summary, MetSyn does not decrease hypercapnic cerebral vasodilation. ROS alone are not obligatory or inhibitory for hypercapnic cerebral vasodilation. Rather, ROS interact with COX to account for the vast majority (>70%) of hypercapnic cerebral vasodilation in healthy and MetSyn adults.Support or Funding InformationAHA PRE7390038
Aerobic Exercise Dampens Acute Hypertension‐Induced Vascular Oxidative Stress
Authors: Robinson Austin T , Fancher Ibra Seaphus , Bian Jing‐Tan , Ali Mohamed M , Sudhahar Varadarajan , Ushio‐Fukai Masuko , Fukai Tohru , Levitan Irena , Phillips Shane A 
Published: November 2023

Regular exercise prevents endothelium dysfunction (ED) following acute strenuous physical exertion. Acute strenuous exertion induces ED via exposing the vascular endothelium to transient hypertension (HTN). The purpose of this study was to determine the mechanisms through which regular exercise may protect the endothelium against HTN‐induced ED. Twenty‐eight 14–18 week mice were assigned to voluntary wheel running for two weeks (EX; mean: 7 miles/day) or control (CON). Hind limb subcutaneous adipose resistance arteries (RAs) were dissected and cannulated for measures of flow induced dilation (FID) with and without exposure to high intraluminal pressure (HILP; 110mmHg) and pharmacological agents including the nitric oxide synthase (NOS) inhibitor L‐NAME (100 μM), hydrogen peroxide (H2O2) scavenger PEG‐Cat (500 U/ml, and the angiotensin receptor blocker losartan (10 μM). Fluorescence microscopy was used to determine O2− and H2O2 production and western blot was used to determine NOX2 and SOD content. Following exposure to acute HILP, FID was preserved in EX and reduced in CON but rescued with losartan, NADPH oxidase inhibition (VAS2870; 2 μM) and the anti‐oxidant Apocynin (50 μM). Furthermore, preserved FID in EX was significantly reduced in the presence of PEG‐Cat compared to L‐NAME. CON expressed more NOX2 and produced greater amounts of O2− following transient HTN while EX expressed more SOD and produced more H2O2. These findings suggest regular exercise prevents HTN‐induced reductions in FID and the mechanism involves attenuating RAAS activation of NOX2 generation and dismutation of O2− to H2O2.Support or Funding InformationNHLBI K23HL85614, RO1HL095701, and HL095701‐01A2S
Effect of Prolonged Adenosine Infusion on Resting Forearm Vasodilatory Responses and Exercise Hyperemia
Authors: Ranadive Sushant , Shepherd John‐Roger Mohan , Dinenno Frank , Curry Timothy , Joyner Michael 
Published: November 2023

High doses of adenosine (ADO) infused over a prolonged period (3 hours) produces marked vasodilation. However, this vasodilation wanes over time in an isolated canine skeletal muscle preparation. To our knowledge the waning of vasodilation with high doses of ADO has not been shown in humans. In addition, ADO plays a controversial role in exercise hyperemia. Therefore, our primary hypothesis was that in humans during a continuous three‐hour intra‐arterial infusion of a high dose of ADO (23 μgrams ·100 mL forearm vol−1·min−1) skeletal muscle blood flow would wane over time. Our secondary hypothesis was exercise hyperemic responses during ADO administration would be similar compared to control. Nine healthy young participants (29 ± 2 years) performed rhythmic handgrip (HG) exercise bouts (20% of maximum) during saline and 180 minutes of continuous ADO infusion. Forearm vascular conductance (FVC; ml min−1 (100 mmHg)−1) was calculated from measured forearm blood flow and mean blood pressure. FVC during minute 5 versus minute 175 during ADO infusion were 24.22 ± 3.2 versus 23.24 ± 1.95 ml min−1 (100 mmHg)−1 respectively (p>0.05). FVC during exercise increased significantly from baseline (4.78 ± 0.63 to 31.13 ± 4.17 ml min−1 *100 mmHg−1) during saline infusion and from (24.22 ± 3.23 to 56.33 ± 4.82 ml min−1 *100 mmHg−1) at five minutes and 21.99 ± 1.25 to 59.16 ± 5.21 seen at 150 minutes during ADO infusion. There was no significant difference in the delta FVC (exercise FVC – baseline FVC) between saline exercise bout versus ADO exercise bout (26.34 ± 3.75 versus 32.11 ± 5.55 ml min−1 *100 mmHg−1). Our findings show that contrary to the animal model, ADO vasodilatation does not wane in humans. Also, the vasodilator responses to exercise are similar during saline and prolonged ADO infusion compared to control condition. These findings suggest a minimal role of ADO in exercise hyperemia.Support or Funding InformationSupported by National Institutes of Health Research Grants HL‐119337 (to M.J. Joyner and F.A. Dinenno) and by CTSA UL1 TR000135. The Caywood Professorship (M.J. Joyner) via the Mayo Foundation also supported this research.
Effect of partial denervation mitochondrial ROS generation in skeletal muscle
Authors: Pollock Natalie , Staunton Caroline Amy , Vasilaki Aphrodite , McArdle Anne , Jackson Malcolm 
Published: November 2023

Dramatic changes in mitochondrial generation of hydrogen peroxide (H2O2) are observed in the skeletal muscle of rodents following experimental nerve transection. The consequences of this denervation are well documented. We have hypothesised that denervation of even a limited number of fibers, such as that observed in muscles during ageing, could influence mitochondrial H2O2 generation by both denervated and innervated fibers throughout the muscle.Thy1‐YFP mice (expressing YFP in neuronal cells only) underwent surgical transection of one of the 3 nerve branches entering the anterior tibialis (AT) muscle. Generation of H2O2 by mitochondria in permeablised fibers with intact mitochondria from 4 different regions of the AT muscle was assessed using Amplex Red. Confocal microscopy of the excised muscle allowed us to visually track and map the morphological changes in both muscle and nerve which accompanied the post‐surgical changes in H2O2 generation.Following partial denervation, oxidation of Amplex red was increased by 40–70 fold in the bundles of fibers from all regions of the AT muscle. This increase was comparable to those observed in fully denervated muscles in our previous experiments.Imaging techniques have demonstrated that NMJ morphology following partial denervation is variable and undergoes rapid changes. At 24 hrs following surgery, the site of surgical denervation is clearly identifiable by the loss of nerve endplates, with no evidence of post‐synaptic changes. By 7 days post‐surgery, the morphological status of the NMJ's is highly variable across the entirety of the muscle.Cross‐sectional area analysis has revealed that even partial denervation is sufficient to cause muscle fibre atrophy, with no clear correlation between the site of initial injury and fibre cross‐sectional area.Taken together, these data show that mitochondria in innervated muscle fibers are affected by denervation of adjacent fibers and contribute to the increased H2O2 generation. Thus data support our hypothesis that loss of innervation in some muscle fibres is sufficient to disrupt the regulation of mitochondrial H2O2 generation with consequences for the entire muscle, an effect which may be mirrored in sarcopenia.Support or Funding InformationSupported by the UK Biotechnology and Biological Sciences Research Council (BBSRC).
Aldosterone Acutely Enhances Coronary Artery Contractile Responsiveness without Inducing Endothelial Dysfunction
Authors: Cleeton Hannah M. , Meuth Alexander I , Bender Shawn B 
Published: November 2023

Inappropriate activation of the renin‐angiotensin‐aldosterone system (RAAS) contributes to increased contractility of the vasculature in many disease states. Activation of vascular mineralocorticoid receptors (MR) has recently been implicated as an important regulator of vascular function. In vascular smooth muscle, genomic mechanisms of MR activation have been implicated in vascular contractility, however, little is known regarding non‐genomic MR signaling as a modulator of vascular contractility. Based on available evidence, we hypothesized that acute aldosterone incubation of murine coronary arteries ex vivo would enhance coronary contractility via non‐genomic MR activation in smooth muscle cells (SMC). Wire myography experiments were conducted on isolated coronary arteries from C57BL/6J mice. Contractile responses to KCl (10mM–45mM) were determined by repeated measures design before and following one hour aldosterone treatment (10nM or 100nM). KCl induced dose‐dependent coronary vasoconstriction that was enhanced by aldosterone incubation in a dose dependent fashion. Vasoconstriction to 20mM KCl was doubled following incubation with 10nM aldosterone and increased >3‐fold following incubation with 100nM aldosterone. Pretreatment with the selective MR antagonist eplerenone (10μM) did not significantly reduce enhanced KCl vasoconstriction in response to 100nM aldosterone. Furthermore, endothelium‐dependent coronary vasodilation to acetylcholine was unchanged following one hour aldosterone incubation regardless of dose. In conclusion, acute aldosterone incubation enhances coronary vasoconstrictor responses to KCl that, at least in response to high dose aldosterone (100nM), is not dependent on MR activation. Importantly, this effect appears to be smooth muscle‐specific and not secondary to aldosterone‐induced endothelial dysfunction as acute aldosterone incubation did not impair endothelium‐dependent coronary vasodilation. These results highlight important vascular cell‐specific effects of aldosterone that may underlie enhanced coronary contractility in disease states associated with inappropriate RAAS activation.Support or Funding InformationFunded by VA CDA‐2 IK2 BX002030 and the American Physiological Society.
Effect of chronic stress and aerobic exercise on glycemic control in rats
Authors: Marcondes Fernanda Klein , Sanches Andrea , Costa Rafaela , Casarini Dulce Elena , Cunha Tatiana Sousa 
Published: November 2023

We have previously shown that chronic mild and unpredictable stress (CMS) induced endothelium dysfunction and insulin resistance in rats. Physical exercise is recognized to provide better glycemic control. Thus, the aim of this study was to evaluate the effect of moderate exercise on the response to oral glucose tolerance test (OGTT) of rats submitted to CMS. Male Sprague‐Dawley rats were divided into four groups: 1) Control, 2) Exercise, 3) CMS and 4) Exercise plus CMS (n=7–9). CMS protocol consisted on application of different stressors, 7 days per week (wk) during 3 wk (5, 6 and 7th wk of protocol). The physical exercise was performed after a period of adaption on the treadmill and consisted of an intensity of 50–70% of the maximal exercise test, 5 days per wk, and 1 hour per day (during 8 wk). Data were analyzed by ANOVA bifatorial (p<0.05). All procedures were approved by Institutional Ethics Committee. Exercise, CMS and Exercise plus CMS presented higher corticosterone plasma level in comparison with Control group (p < 0.05). Exercise (781.1 ± 17,2 mmol × min/L) and Control (842.9 ± 15.5 mmol × min/L) group presented lower area under the curve of glucose during OGTT in comparison with Exercise plus CMS (872.0 ± 12,9 mmol × min/L) and CMS (879.5 ± 11.5 mmol × min/L) group, respectively (p<0.05). These data show that aerobic training has not been able to abolish the impairment of glucose tolerance induced by CMS.Support or Funding InformationFAPESP, CAPES, CNPq, FAEPEX‐UNICAMP.
Mouse SERCA2b is Critical in Compensatory Response to High Fat Diet by Maintaining Pancreatic β Cell Proliferation
Authors: Tong Xin , Kono Tatsuyoshi , Anderson‐Baucum Emily , Shull Gary , Evans‐Molina Carmella 
Published: November 2023

Type 2 diabetes (T2D) affects over 380 million individuals worldwide and is characterized by peripheral insulin resistance and inadequate insulin secretion from the pancreatic β cell. During the development of T2D and in the face of increasing peripheral insulin resistance, the β cell undergoes a compensatory response to both increase insulin production and secretion. Here, we tested the hypothesis that intact activity of the sarco‐endoplasmic reticulum calcium ATPase (SERCA) pump, which transports 2 calcium molecules into the ER lumen during each catalytic cycle and is responsible for maintaining a robust ER calcium pool, is a critical determinant of the β cell's adaptive response to diet‐induced obesity. To this end, mice with a total body heterozygous deletion of SERCA2 (S2HET) and wild‐type littermate controls (WT) were placed on high fat diet (HFD) containing 45% of kilocalories from fat for 16 weeks. Compared to WT controls, S2HET mice showed equivalent body weight gain and fat content. Interestingly, S2HET mice demonstrated fasting hyperglycemia, hypoinsulinemia, and significantly impaired glucose tolerance. Insulin sensitivity and insulin signaling in liver, skeletal muscle, and adipose tissue were not different between S2HETs and WT controls, suggesting a primary defect at the level of the β cell. Histologic analysis of pancreatic sections obtained after 16 weeks of HFD revealed significantly reduced β cell mass as well as reduced β cell proliferation in S2HET mice. To define mechanisms underlying these observations, a SERCA2 deficient rat insulinoma cell line (S2KO INS‐1) was created using CRISPR/Cas9 technology. At baseline, thymidine incorporation was reduced in S2KO INS‐1 cells. Cell cycle analysis revealed a dramatic shift towards decreased proliferation and a G1/S block, while SERCA2b restoration by adenoviral transduction was able to fully rescue these defects. In the meantime, we observed the expression of adaptive and terminal ER stress markers including Bip, Dnajc3, hsp90b1, Pdia4 and spliced Xbp‐1 were elevated in both S2KO INS‐1 cells and isolated S2HET islets. Consistent with this, further analysis by polyribosomal profiling analysis revealed a translational initiation block in both S2KO cells and islets isolated from S2HET mice. In aggregate, these data suggest that impaired SERCA2 activity and altered ER calcium homeostasis lead to increased β cell ER stress and impaired proliferation, thereby limiting the β cell compensatory response to diet‐induced obesity.Support or Funding InformationNIH R01 DK 093954 and VA Merit Award 1I01BX001733
Paracrine GABA and insulin restrain pancreatic α‐cell proliferation in islets of Langerhans
Authors: Feng Allen L. , Xiang Yun‐Yan , Gui Le , Feng Qingping , Lu Wei‐Yang 
Published: November 2023

In type 1 diabetes loss of pancreatic β‐cells is followed by a rapid increase of α‐cells. However, the underlying mechanisms are not fully understood. β‐cells express glutamic acid decarboxylase (GAD) and produce a large amount of γ‐aminobutyric acid (GABA), which, together with insulin, inhibits α‐cell secretion of glucagon. We investigated the role of GABA and insulin in the regulation of α‐cell proliferation in vitro and in vivo. Results showed that treatment with insulin and the type‐A GABA receptor (GABAAR) agonist muscimol significantly decreased intracellular [Ca2+], phosphorylated mammalian target of rapamycin (p‐mTOR) and proliferation rate in cultured αTC1‐6 cells. Administration of streptozotocin (STZ) to mice caused a substantial decrease of GAD and GABA as well as insulin in β‐cells at 12 hours, which was followed by an upsurge of p‐mTOR in α‐cells at day 1 and a significant increase of α‐cell mass at day 3. Remarkably, treatment with GABA largely restored the level of insulin and GAD in pancreatic β‐cells, and significantly decreased α‐cell mass and hyperglucagonemia in the STZ‐injected mice. These results show that decreases in GABA and insulin in β‐cells increase α‐cell proliferation in type 1 diabetes. We conclude that the paracrine GABA and insulin restrain α‐cell proliferation in islets of Langerhans.Support or Funding InformationCanadian Institutes of Health Research (CIHR)