bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disruption of Adenylyl Cyclase Type 5 Eliminates Gender Differences in Exercise Capacity
Authors: Rynecki Nicole Danielle , Guers John , Zhang Jie , Vatner Dorothy , Vatner Stephen 
Published: November 2023

It is well established that enhanced exercise capacity is related to protection from cardiovascular disease, obesity and contributes to healthy aging. Unlike larger animals and humans, where male animals have a higher exercise capacity, female mice have generally shown to have a greater basal exercise capacity and a greater threshold for exercise training improvement. Relatively few studies have examined gender differences in models with enhanced exercise capacity. Since male mice with disruption of adenylyl cyclase type 5 (AC5) have greater exercise capacity than their wild type (WT) littermates, the goal of this investigation was to determine if female AC5 knock out (KO) mice have even greater treadmill exercise capacity than their male littermate. Untrained WT female mice exhibited 21 ± 4% greater maximal exercise capacity for distance (475 ± 19 m) than age‐matched males (males: 389 ± 19 m; p<0.05). In part this could be explained by lower weight of females, although cardiac work was also increased by 13 ± 3.5% in untrained females. When mice were exercise‐trained for 4 weeks by running for 1 hour per day, the exercise‐trained mice had a similar gender disparity with females running 23 ± 8.5% greater distance than age‐matched trained males. We then examined exercise capacity in male and female AC5 KO mice. As we found before, male AC5 KO mice without exercise training performed better (835 ± 32 m) than even female exercise‐trained WT (716 ± 42 m). Surprisingly, female AC5 KO mice performed exercise no better (863 ± 44 m) than the male AC5 KO mice, and work performed was no longer greater in females (27.8 ± 1.4 J) than males (27.9 ± 1.3 J). These data suggest that a cyclic AMP mechanism may be involved either in these gender differences or in the ability to attain maximal exercise capacity.Support or Funding InformationThis study is supported by NIH grant: R01 HL106511.
Exercise combined with low‐level GABAA receptor inhibition up‐regulates the expression of neurotrophins in the motor cortex
Authors: Takahashi Kazuma , Maejima Hiroshi , Ikuta Gaku , Asaka Tadayoshi , Mani Hiroki 
Published: November 2023

Neurotrophins play a crucial role in neuroplasticity, neurogenesis, and neuroprotection in the central nervous system. Exercise is known to increase the expression of brain‐derived neurotrophic factor (BDNF) in the brain. Several animal studies have evaluated the tonic inhibition of GABAergic synapses to enhance hippocampal plasticity as well as learning and memory, whereas the effects of GABAergic inhibition on plasticity in the cerebral cortex related to motor learning are not well characterized. The objective of the present study was to examine the interactive effect of low‐level GABAA receptor inhibition and exercise on the expression of neurotrophins including BDNF in the murine motor cortex. ICR mice were randomly distributed among 4 groups based on two factors of GABAA receptor inhibition and exercise, i.e. a control group, an exercise group, a bicuculline group, and an exercise plus bicuculline group. We administered GABAA receptor antagonist, bicuculline intraperitoneally to the mice (bicuculline and exercise plus bicuculline group) at a non‐epileptic dose of 0.25 mg/kg, whereas the mice (exercise and exercise plus bicuculline group) were exercised on a treadmill for 1 hour every day. After two week intervention, the expression of mRNA and protein abundance of neurotrophins in the motor cortex was assayed using Real time PCR and ELISA. BDNF gene expression was significantly increased by approximately 3‐fold in the bicuculline group relative to the control, exercise, and bicuculline plus exercise groups. Protein abundance of BDNF expression was significantly increased by approximately 3‐fold in the bicuculline plus exercise group relative to other groups. Therefore, the present study revealed that combined GABAA receptor inhibition and moderate aerobic exercise up‐regulated BDNF protein expression in the motor cortex without producing side effects on motor or cognitive functions. Alterations in BDNF expression could positively contribute to plasticity by regulating the balance between EPSPs and IPSPs in the motor cortex and thus provide a more appropriate neuronal condition for motor learning and recovery.Support or Funding InformationThis work was supported by JSPS KAKENHI Grant 24500619.
Influence of Exercise and Maternal Lipids during Pregnancy on Neonatal Size
Authors: May Linda E , Moyer Carmen M , Newton Ed , Strickland Diana , Isler Christy , Haven Kelley , DeVente Jim , Chasan‐Taber Lisa , Kelley George , Fang Xiangming 
Published: November 2023

We hypothesized that exercise during pregnancy and maternal BMI will be significant predictors of neonatal size. This hypothesis was tested by analyzing maternal and neonatal measurements. Women were exercise trained throughout pregnancy for 20 wks at moderate intensity for 150 min/wk. Maternal pre‐pregnancy BMI was self‐reported; and lipids were measured before and after exercise intervention. Fetal (36 wk) weight was acquired via ultrasound and neonatal measures were acquired via birth records. Data from 36 uncomplicated pregnancies (27 exercise,9 control) were analyzed. Although exercise is not a significant predictor of neonatal size, exercise intervention changed maternal lipid levels. We found that a significant predictor of neonatal BMI is maternal LDL levels after exercise intervention training. A significant predictor of neonatal ponderal index is maternal triglycerides and LDL levels after exercise intervention training. Surprisingly, we have found exercise during pregnancy only indirectly influences neonatal measures by changing maternal lipid levels. These results suggest maternal lipids influence neonatal size, but exercise during pregnancy can help regulate this influence. These data further support the benefits of exercise during pregnancy on positive neonatal outcomes.Support or Funding InformationECU, 15GRNT24470029
Enhanced microvascular function in the cutaneous circulation with platelet inhibition is not related to alterations in blood viscoelastic properties
Authors: Garner Tyler Bruce , Dahmus Jessica , Manning Keefe , Alexander Lacy 
Published: November 2023

Platelet inhibition with aspirin and/or clopidogrel are part of a comprehensive strategy for the primary and secondary prevention of cardiovascular disease, respectively. In the cutaneous microcirculation, treatment of clopidogrel (CLO) but not aspirin (ASA) increases cutaneous microvascular relaxation in response to reactive hyperemia. CLO is mechanistically distinct from ASA in that it works through inhibiting the platelet P2Y12 receptor and may change blood viscosity and thus the shear stimulus on the microcirculation. In this study, we sought to determine if platelet inhibition with CLO changes whole blood viscoelastic properties and is related to increased microvascular function. Nine middle‐aged healthy subjects (5 men, 4 women; 56 ± 1 yr) participated in a randomized, double blind, placebo‐controlled crossover experiment. Treatment phases included a sucrose placebo, CLO (75 mg; Bristol‐Myers Squibb), and ASA (81 mg; Bayer) for 7–10 days with a two week washout period between each treatment. On the final day of treatment, laser Doppler flux (LDF) was measured during a standardized 5 minutes reactive hyperemia protocol and area under the curve (AUC) and total hyperemic response (THR) were calculated and normalized to maximal cutaneous vascular conductance (%CVCmax: 43°C and 28 mM sodium nitroprusside). Blood viscoelasticity was measured using a Vilastic‐3 viscoelasticity analyzer at 2 Hz across a physiologically relevant shear rate range of 25 to 1000 s−1. Blood temperature was maintained at time of draw using a heat exchanger. CLO and ASA did not change hematocrit relative to the placebo control (41.6 ± 0.9, 41.9 ± 0.6, and 41.5 ± 0.7 % respectively). AUC and THR increased in the CLO trial (AUC = 3783 ± 342, THR = 2306 ± 266 %CVCmax * s; P<0.0001 vs. placebo) but there was no difference between ASA (AUC = 3101 ± 325, THR = 1695 ± 197 %CVCmax * s) and placebo (AUC = 3000 ± 283, THR = 1675 ± 170 %CVCmax * s, P>0.05) Apparent kinematic viscosity and elasticity was unchanged in either CLO or ASA treatment relative to placebo across the entire range measured when normalized to a hematocrit of 45 %. 7–10 days of CLO or ASA does not change hematocrit or blood viscoelastic properties in healthy humans and is not related to functional measures of microvascular function (p>0.05). Improvements in cutaneous microvascular function by CLO is not a result of shear‐stress induced vasodilation, further indicating that CLO may alter sensory nervous activity and/or endothelium‐derived hyperpolarizing factor mechanisms.Support or Funding InformationNIH R01 HL093238‐07
Effects of Glycyrrhetic Acid and other Chemical Components of Shakuyakukanzoto on Cutaneous Microcirculation in Humans
Authors: Dillon Gabrielle A. , Ranadive Sushant M. , Joyner Michael J. , Eugene Andy R. , Tasaki Kazuyo M. , Noble Denis M. 
Published: November 2023

The purpose of this study was to explore dose dependent vasodilation responses of the individual compounds of Shakuyakukanzoto (SKT), a 1:1 combination of extracts from Paeony and Licorice roots: glycyrrhetic acid (GA), paeoniflorin (PF), and isoliquiritigenin (ISO). 20 young, healthy participants (13M/7W) had four intradermal microdialysis fibers placed in the forearm skin for local delivery of: 1) control (diluent), 2) GA, 3) PF, or 4) ISO at doses of 1, 10, 50, or 100 μm. Cutaneous red cell flux, an index of skin blood flow, was measured by laser‐Doppler flowmetry. Blood pressure (BP) was monitored continuously during fixed measurement periods via finger photo‐plethsmography (Finapres). Cutaneous vascular conductance (CVC) was derived as red cell flux divided by BP and was normalized as a percentage of baseline (%CVCbl, saline at 4 μl/min) and the maximum CVC (%CVCmax, 28mM sodium nitroprusside at 4 μl/min, local temperature 43°C). Mean CVC did not statistically differ between baseline and individual compound plateau (average of last 5 minutes of infusion) at any dose. The peak flux was significantly higher from baseline at doses 50 and 100 μm for control (56.17±13.32 vs. 96.73±20.32 and 44.64±5.68 vs. 80.21±9.54), PF (62.70±10.09 vs. 115.72±16.16 and 62.37±16.2 vs. 150.21±34.26), GA (48.37±4.41 vs. 71.76±7.16 and 58.36±13.68 vs. 91.51±3.41), and ISO (96.50±23.20 vs. 128.57±27.90 and 44.95±8.78 vs. 91.18±20.37) (p<0.05). However, peak CVC was significantly higher only for GA at dose 50 μm, as well as for control and PF at dose 100 μm compared to their respected baselines (GA: 0.60±0.06 vs. 1.01±0.11, control: 0.61±0.09 vs.1.55±0.61, PF: 0.81±0.20 vs. 1.30±0.30, p<0.05). There were no other significant differences between the control and the compounds for change in CVC from baseline to peak (ΔCVC), %CVCbl, or %CVCmax. There were no significant differences between doses 1, 10, or 50 as compared to 100 μm for other variables. These results suggest that the doses may be lower or below the threshold to cause a vasodilatory effect. Future studies that investigate higher doses of these compounds may be needed.Support or Funding InformationThe University of Oxford Systems Biology Project sponsored by Tsumura.
Carotid Vascular Blood Flow in Individuals with Down Syndrome Following Low Body Negative Pressure Challenge
Authors: Wee Sang Ouk , Rosenberg Alexander J. , Kanokwan Bunsawat , Griffith Garett , Baynard Tracy , Fernhall Bo 
Published: November 2023

Individuals with Down Syndrome (DS) exhibit autonomic dysfunction with reduced sympathetic activity, which may cause reduced aerobic capacity and alterations in peripheral blood flow. Carotid vascular function has been considered as a marker of future cardiovascular events. However, changes in carotid blood flow and vascular conductance in response to sympathoexcitation are not well characterized in persons with DS, carotid stiffness responses to exercise differ between individuals with DS and controls.PurposeTo examine the differences in hemodynamics, carotid vascular reactivity and blood flow following sympathoexcitation using lower body negative pressure (LBNP) in individuals with and without DS.Methods13 young (18 < age <40 yrs) individuals with and without DS (DS=6) participated in this study. Changes in hemodynamics and carotid vascular reactivity (BP, carotid diameter, carotid flow and vascular conductance) were measured before, during and after LBNP (−20 mmHg).ResultsBaseline hemodynamics where not different between the group with DS and controls. The group with DS showed an altered response in conductance to LBNP, when compared to controls with large effect size (η2 = 0.138). In addition, carotid blood flow exhibited a large effect size (η2 = 0.242) for a group interaction. During recovery, the group with DS showed an increase in BF, whereas control group exhibited decrease in BF. These changes occurred without differential changes in carotid diameter and blood pressure.ConclusionsOur results demonstrate the tendency of reduced vascular reactivity in individuals with DS to sympathoexcitation, demonstrated by large effects sizes. Our findings indicate altered blood flow control in persons with DS, attributable to autonomic dysfunction. Larger sample sizes will be needed to confirm these findings.

DS (N = 6)
Control (N = 7)

Baseline
LBNP (−20mmHg)
Recovery
Baseline
LBNP (−20mmHg)
Recovery

Carotid SBP (mmHg)
118 ± 5
111 ± 4
119 ± 5
126 ± 5
114 ± 4
121 ± 4

Carotid DBP (mmHg)
69 ± 4
68 ± 3
68 ± 3
76 ± 3
73 ± 2
77 ± 3

Carotid MAP (mmHg)
87 ± 5
84 ± 3
88 ± 4
96 ± 4
90 ± 3
95 ± 4

Carotid Blood Flow (ml/min)
378.0 ± 110.3
394.1 ± 115.3
399.9 ± 112.2
539 4 ± 102.1
552.6 ± 106.8
500.1 ± 103.9

Carotid Vascular Conductance (ml/min/100mmHg)
25.3 ± 3.6
29.0 ± 4.6
28.1 ± 4.0
32.0 ± 3.3
35.1 ± 3.8
30.7 ± 3.6

Mean ± SEM
Aerobic training restores endothelial function in intrauterine growth restricted rats: Possible involvement of eNOSThr495 phosphorylation
Authors: Oliveira Vanessa , Victorino Livia , Silva Sebastião Donato , Fernandes Tiago , Akamine Eliana , de Carvalho Maria Helena Catelli , de Oliveira Edilamar Menezes , Michelini Lisete Compagno , Franco Maria 
Published: November 2023

PurposeTo evaluate the effects of aerobic training on vascular reactivity in adult male offspring submitted to intrauterine growth restriction.MethodsProcedures approved by Ethics Committee of UNIFESP (836880). Pregnant Wistar Rats were submitted to Ad libitum or 50% of Ad libitum diet throughout gestation. At birth, pups were weighted. Adult Male offspring of both groups were assigned to Sedentary Control (SC), Sedentary Restricted (SR), Trained Control (TC) and Trained Restricted (TR). After AT (10 weeks, 5 days/week, 1h/day, 50–60% of maximum exercise capacity) femoral artery was cannulated to register mean arterial blood pressure (BP) and heart rate (HR). The vasodilatation endothelium‐dependent and endothelium‐independent were assessed by concentration‐response curves to Acetylcholine (ACh:10–9M‐3X10‐5M) and Sodium Nitroprusside (SNP:10‐9M‐10‐6M), respectively in thoracic aorta rings. In addition, we evaluated in thoracic aorta: protein expression of total eNOS, p‐eNOSSer1177, and p‐eNOSThr495 using western blotting, and nitric oxide concentration by NO analyzer. Results are shown as mean ± EPM, test t de student or Two‐way ANOVA following Bonferroni were used.ResultsIUGR was confirmed by birth weight (Control:7.01±0.34g vs. Restricted:4.3±0.08g). AT‐restored BP in TR (SC:118±3mmHg; TC:110±2 mmHg; SR:129±2 mmHg; TR:110±4 mmHg) and lead to a reduction in HR (SC:355±13bpm; TC:321±4 bpm; SR:343±4 bpm; TR:309±7 bpm). AT normalized the relaxation to ACh (SC:92.18±2.7%; TC:90.05±2.04%; SR:65.04±4.4%; TR:93.35±1.7%) in aorta from IUGR rats, whereas vasodilatation to SNP was not altered (SC:98.45±2.38%; TC:97.84±1.68%; SR:93.97±2.64%; TR:97.64±0.90%). p‐eNOS Ser1177 expression was similar among groups (data not show). However, AT‐reduced the increased p‐eNOSThr495 found in aorta from RT group (SC:0.53±0.03; TC:0.51±0.10; SR:0.86±0.06; TR: 0.59±0.04). Nitric oxide concentration was increased in RT (SC: 426.2±63.03μM/mg; TC: 349±46 μM/mg; SR: 217.8±18.22 μM/mg; TR: 355±53 μM/mg).ConclusionOur results indicated that AT‐restores endothelial function in intrauterine growth restricted rats, in part due to reduction in p‐eNOSThr495 expression associated to increase in nitric oxide concentration in thoracic aorta.Support or Funding InformationFAPESP: 2013/00311‐6
Activation of Protease‐Activated Receptor 2 Directly Mediates Cutaneous Vasodilatation but Not Sweating in Humans In Vivo: Roles of Nitric Oxide Synthase and Cyclooxygenase
Authors: McNeely Brendan Douglas , Fujii Naoto , Zhang Sarah Y. , Daquan Mercy O. , Kenny Glen P. 
Published: November 2023

Protease‐activated receptor 2 (PAR2) is present in the endothelial cells of skin microvessels and eccrine sweat glands in humans. Notably, this receptor has been shown to play a role in the vascular control of larger arteries and the control of epidermal permeability. However, it remains unclear if PAR2 functionally contributes to the regulation of cutaneous blood flow and sweating in humans. Therefore, the objective of the current study was to determine whether the activation of PAR2 directly stimulates cutaneous vasodilation and sweating through nitric oxide synthase (NOS) and cyclooxygenase (COX) mediated mechanisms. In twelve young males (29±5 years), cutaneous vascular conductance (CVC, measured via laser‐Doppler perfusion units/mean arterial pressure) and sweat rate (measured via ventilated capsule) were evaluated at four intradermal microdialysis forearm skin sites that were constantly perfused with either 1) lactated Ringer (Control), 2) 10 mM Nω‐nitro‐L‐arginine (NOS inhibitor), 3) 10 mM ketorolac (COX inhibitor), or 4) a combination of 10 mM Nω‐nitro‐L‐arginine + 10 mM ketorolac. The PAR2 agonist (SLIGKV‐NH2) was co‐administered at all sites in a dose‐dependent fashion (0.06, 0.18, 0.55, 1.66, and 5 mM, each for 25 min). Throughout the protocol, participants rested in a semi‐recumbent position in a thermoneutral room (23°C). Responses were compared at baseline and the last 5 min of each dose administered. The highest dose of SLIGKV‐NH2 (5 mM) increased CVC from baseline (BL) at the Control site (BL: 15 ± 8% CVCmax, 5 mM: 37 ± 22% CVCmax; P ≤ 0.01). This increase in CVC associated with PAR2 activation was attenuated by NOS inhibition with or without simultaneous COX inhibition (Control: 37 ± 22%CVCmax, NOS inhibition: 25 ± 16% CVCmax, NOS+COX inhibition: 23 ± 16% CVCmax; both P ≤ 0.05). However, COX inhibition alone had no effect on the PAR2 mediated increase in CVC at all doses (all P > 0.05). No increase in sweat rate was measured at any administered dose of SLIGKV‐NH2 irrespective of the agent co‐administered (all P > 0.05). In conclusion, we show that in normothermic resting humans, in vivo activation of PAR2 directly mediates cutaneous vasodilation through NOS‐dependent mechanisms without any contribution of COX mediated pathways. Alternatively, the same activation of PAR2 does not lead to increases in forearm sweat rate.Support or Funding InformationThis study was supported by the Natural Sciences and Engineering Research Council of Canada (Discovery grant, RGPIN‐06313‐2014; Discovery Grants Program ‐ Accelerator Supplement, RGPAS‐462252‐2014; funds held by Dr. Glen P. Kenny).
Impact of Sleep Disordered Breathing on Carotid Body Size
Authors: Petersen‐Jones Humphrey G. , Welch Brian T. , Eugene Andy R. , Brinjikji Waleed , Kallmes David F. , Curry Timothy B. , Joyner Michael J. , Limberg Jacqueline K. 
Published: November 2023

Post‐mortem analyses have identified carotid body hypertrophy in conditions of chronic hypoxemia, including sleep apnea; however, post‐mortem assessment limits the clinical relevance of such findings. We tested the hypotheses that: 1) carotid body size can be detected in living individuals by computed tomographic angiography (CTA), and 2) patients with sleep disordered breathing [Apnea Hypopnea Index (AHI) ≥ 30 events/hour] exhibit larger carotid bodies than those without sleep disordered breathing (AHI < 5 events/hour). A chart review was conducted from patients seen at the Mayo Clinic between January 2000 and February 2015 who had undergone neck CTA and polysomnography. From an initial pool of 583, 109 patients met our strict inclusion criteria. Widest axial measurements of the right and left carotid bodies were performed independently by two radiologists blinded to condition and average carotid body size was calculated for each patient of interest. Carotid body identification was possible in 81% of patients. Intra‐class correlation coefficients ranged from 0.93 to 0.95 (right carotid body: 0.93; left: 0.94; average: 0.95). From subjects with identifiable carotid bodies, widest axial measurements were greater in patients with high AHI (n=32; right: 2.9±0.2mm, left: 3.1±0.2mm, average: 3.0±0.1mm) compared to patients with low AHI (n=46; right: 2.5±0.1mm, left: 2.7±0.1mm, average: 2.6±0.1mm; p=0.04, p=0.04, p=0.02, respectively). Because participants in the high AHI group were significantly older than those in the low AHI group (65±2 years vs. 50±2 years; p<0.01), an analysis of covariance was performed to control for the influence of age on carotid body size. After adjusting for age, no differences in carotid body size were observed between the patient groups (p=0.45, p=0.59, p=0.54 for right, left, and average carotid body, respectively). Main findings are two‐fold: 1) carotid body size can be identified by CTA in approximately 80% of patients with good inter‐observer agreement, and 2) adults that exhibit sleep disordered breathing do not have larger carotid bodies when compared to controls, after adjusting for age.Support or Funding InformationThis work was supported by the National Institutes of Health [grant numbers T32 GM008685 (ARE), R01 DK090541 (MJJ)].
The Brain, Not the Kidney, is the Source of Erythropoietin in Response to Hypoxic Hypoxia
Authors: Allwood Melissa A , Romanova Nadya , Brunt Keith R , Simpson Jeremy A 
Published: November 2023

Erythropoietin (EPO), the principle regulator of erythropoiesis, is central to our understanding of tissue hypoxia. For over a century, the kidney has been regarded as the primary site of EPO production. While multiple extra‐renal sources have been identified, their physiological significance remains largely uninvestigated. Further, studies investigating the source of EPO production use severe (non‐survivable) levels of hypoxia, despite that levels encountered in most pathophysiological states are mild to moderate. The assumption being that the response to less severe hypoxic stimuli is linearly scaled. Our objective was to investigate whole‐body EPO production in response to clinically‐relevant levels of hypoxia. We performed a multi‐organ, temporal analysis of EPO expression in response to moderate (FIO2 = 0.15) and severe (FIO2 = 0.09) hypoxic hypoxia. Using the Cre‐lox system, we proved that the brain, and not the kidney, was the sole responder to moderate hypoxia and the primary responder to severe. Thus, the erythropoietic response to hypoxia involves multiple tissues in a degree‐ and duration‐dependent manner with the brain as the first and primary site of EPO production. These data identify a critical shift in our understanding of oxygen carrying capacity in hypoxic hypoxia from peripheral to central regulation.Support or Funding InformationThis work was funded in part by grants from the Canadian Institutes of Health Research (JAS; Grant # MOP111159) and the Natural Sciences and Engineering Research Council of Canada (JAS). JAS is also a new investigator with the Heart and Stroke Foundation of Ontario.