bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exercise‐like mechanical stimulation improves myogenic responses in aged skeletal muscle resistance arteries
Authors: Shin Song Yi , Seawright John , Trache Andreea , Woodman Christopher 
Published: November 2023

ObjectiveWe tested the hypothesis that exposure to a short‐duration (1 h) increase in intraluminal pressure, to mimic pressure associated with a bout of exercise, would attenuate or reverse the age‐related decline in myogenic constrictor responses in skeletal muscle resistance arteries.MethodsSoleus muscle feed arteries (SFA) from young (4 mo) and old (24 mo) Fischer 344 rats were cannulated and pressurized to 90 (P90) or 130 cmH2O (P130) for 1 h. Following the 1 h treatment period, pressure in the P130 arteries was reduced to 90 cmH2O and SFA were required to develop stable spontaneous tone for 10 min. After stable tone was achieved, myogenic contractile responses were assessed using step‐increases in intraluminal pressure up to 135 cm H2O in 15 cm H2O increments followed by step‐decreases down to 60 cm H2O.ResultsMyogenic vasoconstrictor responses were significantly impaired in old SFA compared to young SFA. Mechanical stimulation with increased pressure for 1 h improved myogenic constriction in old SFA.ConclusionThese results indicate that stimulation with a short‐duration increase in intraluminal pressure, within a range of pressure believed to be present in these arteries during exercise, improves myogenic constrictor responses in aged skeletal muscle resistance arteries.Support or Funding InformationResearch support: AHA grant 0765043Y, AHA grant 4150031, The National Space Biomedical Research Institute through NCC 9–58 and a Sydney and J.L. Huffines Institute of Sports Medicine Graduate Student Research Grant.
Altered Basal Cerebral Perfusion in Adolescents with Insulin Resistance
Authors: Ward Aaron T. , Kellawan J. Mikhail , Peltonen Garrett L. , Carter Katrina J. , Rehm Jennifer L. , Oh Jennifer M. , Carrel Aaron L. , Bendlin Barbara B. , Schrage William G. 
Published: November 2023

Insulin resistance (IR) is associated with reduced macrovascular cerebral blood flow (CBF) and microvascular cerebral perfusion (CP) in middle‐aged adults. Due to the obesity epidemic, more people are affected by IR; however, it is unknown if adolescents with IR have cerebral vascular dysfunction. This is surprising since obese adolescents are known to display abnormal executive function processes. Therefore, we tested the hypothesis that adolescents with IR will exhibit lower basal CBF, as well as CP, in neuronal regions known to be involved in executive function, learning, language, and memory. Five adolescents (15±3 yrs) were divided into groups based on Homeostatic Model of Assessment of Insulin Resistance (HOMA‐IR; Control, CTRL < 4.0, n=2 vs IR ≥ 4.0, n=3). Hemodynamics were measured (HR, SpO2, MAP, ETCO2) and all testing was performed in a fasted state. CBF was measured via 4D MRI utilizing phase contrast‐vastly undersampled isotropic projection reconstruction (PC VIPR). CP was measured by pseudo‐continuous arterial spin labelling (pcASL) MRI, normalized to global pcASL signal. The IR group exhibited higher HOMA‐IR (5.3±0.2 vs 3.3±0.3 p=0.006) and insulin compared to CTRL (28±2 vs 16±3 mU/L; p=0.027). Baseline HR (CTRL 75±6 vs IR 68±3.5 bpm; p=0.185), SpO2 (CTRL 99.0±0.0 vs 96.5±1.3%; p=0.113), MAP (CTRL 75±4.7 vs IR 81.9±5.4 mmHg; p=0.143), and ETCO2 (CTRL 35.5±0.4 vs 40.4±2.0 mmHg; p=0.07) was similar between groups. Total CBF was similar between groups (CTRL 735±79 vs IR 811±115 mL/min; p=0.64) as was CBF in each of the 11 regional arteries measured. Of 14 brain regions examined via pcASL, the IR group exhibited lower CP in the left frontal superior orbital gyrus (4% lower; p=0.002), left angular gyrus (10% lower; p=0.006), right frontal middle gyrus (11% lower; p=0.038), and right frontal superior medial gyrus (11% lower; p=0.017), and tended to be lower in the right frontal superior gyrus (10% lower; p=0.058). Collectively, these regions are notable for language, attention, memory retrieval and cognitive processing of decision making. Taken together, these data indicate preserved total and regional CBF in adolescents with IR. However, preserved bulk CBF appears to mask impairments in microvascular CP in key brain regions linked to learning and memory, which may have implications for long‐term brain health.Support or Funding InformationUniversity of Wisconsin‐Madison Graduate School Pilot Funds
Initial studies of cardiovascular monitoring feasibility using EndoGear 2, a fully implantable telemetry system in swine model
Authors: Goodwill Adam Glenn , Konecny Filip , Pitsillides Koullis , Sosa Margo , Barnard April P , Kiel Alex M , Tune Johnathan D 
Published: November 2023

IntroductionCurrent methodological recommendations for directly translational and clinically relevant models of cardiovascular disease portray large animal models as a mainstay for drug, cell, and gene therapy and for device development and surgical procedure testing. The translational capacity of swine telemetry models has been plagued by an inability to longitudinally assess cardiovascular parameters due to its technological limitations using telemetric instrumentation. Historically, 24‐hour monitoring has required technical staff to physically connect externalized wires which are prone to damage, making the appeal of a fully enclosed automatable data collection system desirable.MethodsWe have performed initial studies to assess cardiovascular parameters employing Transonic EndoGear® 2 (EG2‐Q1S3T‐M25) biotelemetry system on 50kg male domestic swine. At telemeter implantation, a perivascular 2.5 QS flow probe was placed around the left anterior descending coronary artery, 2 ECG leads were attached directly to myocardium, a 3.5F systemic pressure transducer was inserted into the left internal mammary artery and a 7F left ventricular pressure transducer was inserted into the left ventricle via an apical transmural stab. All data were recorded using EMKA IOX software.ResultsAnimals were monitored continuously for 24 hours following the procedure and then for 5 minutes each hour for 1 week subsequently prior to sacrifice. All measurements were within the expected range consistent with previous studies we have performed and animals were able to be reliably monitored for all indicated parameters in real time throughout the monitoring period.ConclusionThese initial studies indicate the feasibility using EndoGear 2 in longitudinal studies monitoring major cardiovascular parameters in untethered and unrestrained swine. The platform enables, for the first time, telemetered monitoring of the coronary artery blood flow using transit time technology.Support or Funding InformationFunded by: R01 HL117620 04
Treatment of long‐term coronary dysfunction in diabetes with mineralocorticoid receptor antagonism: vasomotor control and the MR‐dependent vascular transcriptome
Authors: Brown Scott M , Meuth Alex I , Meers Grace M , Davis J Wade , Rector R Scott , Bender Shawn B 
Published: November 2023

Obesity and diabetes are associated with inappropriate activation of the renin‐angiotensin‐aldosterone system (RAAS) and impaired coronary microvascular function. We recently demonstrated that mineralocorticoid receptor (MR) antagonism with spironolactone (Spiro) treated coronary arteriolar endothelial dysfunction when administered during the development of dysfunction in obesity. Whether MR antagonism can treat long‐term established coronary arteriolar vasomotor dysfunction in diabetes and potential underlying molecular mechanisms have not been investigated. Here, we hypothesized that long‐term diabetes‐associated coronary arteriolar dysfunction will be abrogated by MR antagonism with Spiro involving alterations of the vascular transcriptome. Male Otsuka Long‐Evans Tokushima Fatty (OLETF) rats (29 weeks of age) were treated with Spiro (sc, 20 mg/kg/d) or placebo for 3 weeks. Control, lean Long‐Evans Tokushima Otsuka (LETO) rats were treated with placebo and the onset of coronary microvascular dysfunction was established in separate groups of 5–8, 20, and 32 week old OLETF and LETO rats. At 32 weeks of age, OLETF rats exhibited obesity, hyperglycemia, hypercholesterolemia, normal blood pressure, and reduced circulating aldosterone compared to LETO. Endothelium‐dependent vasodilation of isolated, pressurized coronary arterioles to acetylcholine (ACh) was impaired at 5–8 weeks of age and persisted to 32 weeks in OLETF rats with no change in endothelium‐independent vasodilation to sodium nitroprusside. Further, coronary arteriolar vasoconstriction to endothelin‐1 (ET‐1) and the thromboxane mimetic U‐46619 increased significantly in an age‐dependent manner in OLETF rats. OLETF rats treated with Spiro exhibited similar plasma glucose, insulin, cholesterol, blood pressure, and serum potassium, but elevated circulating aldosterone compared to placebo‐treated OLETF rats at 32 weeks of age. Spiro treatment restored endothelium‐dependent coronary arteriolar vasodilation to ACh and insulin and attenuated coronary vasoconstriction to the L‐type calcium channel agonist BayK‐8644, but not to ET‐1 or U46619 in OLETF rats. RNA sequencing and Ingenuity Pathway Analysis of aortic mRNA from Spiro and placebo‐treated OLETF rats revealed MR‐dependent alterations of gene networks associated with iNOS, ceramide, and TNFR2 signaling. These data support and extend our recently published work by demonstrating that, independent of blood pressure, MR antagonism treats established diabetes‐associated coronary arteriolar endothelial dysfunction, an independent predictor of future cardiovascular events in human patients. In addition, these data highlight novel MR‐dependent alterations of the vascular transcriptome in diabetes that warrant further investigation.Support or Funding InformationSupported by VHA BLR&D BX002030 (SBB) and VHA BLR&D BX001299 (RSR)
No Evidence of Impaired Functional Sympatholysis in Young Obese Adults
Authors: Bunsawat Kanokwan , Grigoriadis Georgios , Wee Sang Ouk , Griffith Garett , Brown Michael D. , Phillips Shane A , Fadel Paul J , Clifford Philip S , Fernhall Bo , Baynard Tracy 
Published: November 2023

In healthy individuals, sympathetic vasoconstriction is blunted in exercising muscles, contributing to the matching of blood flow with metabolic demand. This “functional sympatholysis” may be impaired in young obese adults due to greater sympathetic activation and reduced local vasodilatory capacity of both small and large arteries, but this remains poorly understood. We tested the hypothesis that functional sympatholysis is impaired in obese adults compared with lean counterparts. Participants were 13 lean (female=6; 26±1 yrs; 22.4±0.5 kg/m2) and 14 obese adults (female=7; 27±1 yrs; 32.6±0.6 kg/m2). Lower body negative pressure (LBNP −20 mmHg, 2 min), to evoke reflex‐mediated increases in sympathetic nerve activity, was performed at rest and during steady‐state dynamic handgrip exercise (HG, 30% maximal voluntary contraction; 50% duty cycle). Ultrasonography [brachial diameter, forearm blood flow (FBF), forearm vascular conductance (FVC)], and beat‐to‐beat cardiovascular variables [mean arterial pressure (MAP), heart rate (HR), and cardiac index (CI)] were obtained. FBF and FVC were normalized to lean forearm mass, and CI was cardiac output indexed to body surface area. No group differences were found at rest or during handgrip before LBNP for any variable. LBNP evoked similar decreases in FBF (−18.6±3.0% lean vs. −17.8±3.1% obese) and FVC (−16.6±3.1% lean vs. −14.9±3.1% obese) in the resting forearms of the lean and obese adults (P>0.05 for group). During HG, reductions in FBF (−1.7±3.8% lean vs. −2.0±2.3% obese) and FVC (1.2±4.3% lean vs. 0.1±2.5% obese) to LBNP were blunted in the exercising forearms of both groups (P>0.05 for group). In both lean and obese subjects, LBNP decreased MAP and CI at rest and during HG, but decreased brachial artery diameter and increased HR only during HG (all; P<0.05 for time effect). Our preliminary data suggests that functional sympatholysis is not impaired in young obese adults without comorbidities.Support or Funding InformationThis project is sponsored by the American Heart Association Predoctoral Fellowship (16PRE26430096).

Variable
Group
Rest
Rest with LBNP
30%MVC
30%MVC with LBNP

Brachial Artery Diameter (mm)
Lean
3.46±0.15
3.43±0.14
3.64±0.14
3.62±0.14*

Obese
3.62±0.14
3.60±0.14
3.76±0.14
3.73±0.13*

FBF (mL/min* 100g tissue)
Lean
11±1
8±1*
30±2
30±2

Obese
10±1
8±1*
27±2
27±2

FVC (mL/min* 100mmHg*100g tissue)
Lean
11±1
9±1*
30±2
31±2

Obese
10±1
9±1*
27±2
27±2

MAP (mmHg)
Lean
101±2
99±2*
102±3
100±3*

Obese
100±2
96±2*
103±3
101±3*

HR (bpm)
Lean
62±2
63±2
67±2
71±2*

Obese
64±2
64±2
67±2
72±2*

CI (L/min/m2)
Lean
3.3±0.2
3.0±0.2*
3.7±0.2
3.3±0.2*

Obese
3.0±0.2
2.7±0.2*
3.2±0.2
3.0±0.2*

Data are mean±SE.
P<0.05, time effect.
Brain Homogenates from Alzheimer's Patients Impact Vascular Function
Authors: Zhang Xiancong , Ma Jing , Hajjar Ihab , Sutliff Roy L. 
Published: November 2023

Alzheimer's disease (AD) is characterized by a state of reduced cerebral blood flow, which may partly be secondary to cerebral artery vascular dysfunction. Recent studies have shown that systemic vascular dysfunction may precede Alzheimer's disease. We hypothesize that biochemical changes associated with AD progression can impact vascular function. Homogenates were prepared from temporal lobe samples from patients with or without tauopathies and were categorized into three groups: homogenates with amyloid Tau protein, homogenates with high concentrations of Tau protein but little amyloids, and control.The chronic effects of brain homogenates on vascular function was characterized using isolated wild‐type rat aorta segments incubated with homogenates (0.1% or 1%) for 24 hours. Rat aortas were isometrically mounted and the vascular function was assessed by examining contractile responses to KCl and phenylephrine, and relaxation responses to methacholine and sodium nitroprusside. The acute effect of homogenates on vascular function was measured using wild‐type rat aorta segments after maximal relaxation by methacholine.Preliminary data from chronic studies suggests that, amyloid group patient tissues are less sensitive to methacholine‐dependent relaxation compared to tissue from Tau and control groups(One‐way ANOVA; p<0.05). Preliminary data from acute studies suggests that tissue from the tau group results in more severe contractile effects on maximally relaxed aortas compared to amyloid and control groups. These results are significant because they suggest that biochemical changes associated with AD can impact vascular function. Therefore, these studies suggest that there is an association between AD and vascular dysfunction.Support or Funding InformationSupported by grant AG051633 from NIA./NIH and SIRE to XZ
High Dietary Sodium Reduces Low‐Flow‐Mediated Constriction in Salt‐Resistant Adults
Authors: Ramick Meghan , Lennon‐Edwards Shannon , Rose William , Farquhar William , Edwards David 
Published: November 2023

High dietary sodium has been shown to impair flow‐mediated dilation independent of blood pressure (BP). Low flow‐mediated (LFC) constriction has been proposed as a complementary measure of vascular function in humans. Therefore, the purpose of this study was to test the hypothesis that a high sodium diet would reduce brachial artery LFC in salt‐resistant adults. Additionally, we sought to determine if sex differences existed in the LFC response to high dietary sodium. Twenty healthy, normotensive adults (12 males, 28.8±1.8 yrs; 8 females, 29.8±2.2 yrs) participated in a controlled feeding study. Following a run‐in diet, participants completed 7 days of a low sodium (LS) diet (20mmol sodium/day) and 7 days of a high sodium (HS) diet (300mmol sodium/day) in random order. Diets were designed to be eucaloric and consistent in macronutrient distribution and potassium content. On the last day of the LS and HS diets, a 24‐hour urine was collected and 24‐hour ambulatory BP was assessed. Subjects were classified as salt‐resistant as defined by a change in 24‐hour ambulatory mean arterial pressure (MAP) of ≤5mmHg between the LS and HS diets. On day 7 of the LS and HS diet, LFC was assessed by ultrasound. LFC was calculated as the % change in brachial artery diameter following a 5‐minute distal cuff occlusion. By design, 24‐hour MAP was not different between LS and HS conditions (85±1 vs 84±1 mmHg, p>0.05) whereas urinary sodium excretion (34.8±6.0mmol/24hr vs 269.7±21.6 mmol/24hr, p<0.01) and serum sodium concentration (137.9±0.6mmol/L vs 140.2±0.3mmol/L, p<0.01) increased significantly on the HS diet. LFC was significantly attenuated on the HS diet compared to LS (2.2±0.3% vs 3.3±0.3%). LFC was reduced by HS in both men and women (men: LS 3.8±0.4% vs HS 2.6±0.4%; women: LS 2.6±0.5% vs HS 1.5±0.5%; p<0.05). These data demonstrate that high dietary sodium impairs LFC in salt‐resistant adults providing additional evidence for the adverse vascular effects of dietary sodium independent of BP.Support or Funding InformationResearch funded by NIH grant R01 HL104106
ADAM17 and Impaired Endothelial Insulin Signaling in Type 2 Diabetes
Authors: Restaino Robert M. , Castorena‐Gonzalez Jorge A. , Marshall Kurt D. , Padilla Jaume , Martinez‐Lemus Luis A. 
Published: November 2023

Endothelial dysfunction and impaired insulin signaling are hallmark vascular abnormalities associated with cardiovascular pathogenesis in type 2 diabetes (T2D). Such abnormalities result from impaired insulin‐induced activation of endothelial nitric oxide synthase (eNOS). Hyperglycemia in T2D has been associated with an aggregation of misfolded proteins and resultant endoplasmic reticulum (ER) stress with activation of the unfolded protein response (UPR) in various cell types. Herein, following immunohistochemical examination of mesenteric arteries from T2D patients undergoing bariatric surgery, we show a reduction (P<0.05) in the presence of the insulin receptor alpha subunit (IRα) in all three layers of the vascular wall, notably within the endothelium vs. that in vessels from Non‐T2D individuals. The reduced presence of IRα was associated with an upregulation of ADAM17, an enzyme that is involved in cleavage of outer membrane proteins. We hypothesize that hyperglycemia in T2D induces an upregulation in ADAM17 expression and activity leading to cleavage of IRα from the cell membrane in an ER stress dependent mechanism. To test this hypothesis, serum‐starved human umbilical vein endothelial cells were exposed over night to 5mM glucose (control), 30mM glucose (hyperglycemia) or 0.5μM phorbol 12‐myristate 13‐acetate (PMA, a PKC activator) in 5mM glucose as a positive control of ADAM17 induction. These treatments were administered alone or in combination with the ER stress alleviator tauroursodeoxycholic acid (TUDCA). Cells were harvested for determination of ADAM17 expression and activity. Following treatment with high glucose and PMA, ADAM17 expression was significantly increased (n=7, P<0.05 compared to control) in endothelial cells. Concurrent treatment with TUDCA reduced (n=7, P<0.05) expression of ADAM17 in the hyperglycemic condition. ADAM17 activity was elevated under both hyperglycemic and PMA conditions (fold change from control hyperglycemia=1.97±0.15 A.U., PMA=1.84±0.23 A.U.; n=8, P<0.05) and not affected by TUDCA (p>0.05). Taken together, these results suggest a potential role of ADAM17 in mediating endothelial cell insulin resistance through cleavage of IRα from the cell membrane. This mechanism could be secondary to hyperglycemia‐induced ER stress in T2D.Support or Funding InformationNational Institutes of Health HL‐125503 and DK‐105368 to J.P., HL‐073101 and HL‐088105 to L.A.M‐L.
Heterogeneity of TRPV4 Expression and Function in Endothelial Cells of Different Vascular Beds
Authors: Maishan Mazharul , Lamb David , Lee Warren L , Kuebler Wolfgang M 
Published: November 2023

IntroductionThe ubiquitously expressed calcium channel transient receptor potential vanilloid subtype 4 (TRPV4) has been implicated in various endothelial functions. Specifically, TRPV4 activation triggers endothelial barrier failure. In the lung, TRPV4‐mediated pulmonary edema formation has been reported in response to various triggers including acid aspiration and positive pressure ventilation. Thus, TRPV4 is a promising target for preventing or treating lung injury, but its ubiquitous expression requires investigating potential off‐target effects during therapeutic modulation.MethodsThe present study is working toward this aim by comparing TRPV4 expression and function in human endothelial cells from five different vascular beds: pulmonary (HPMEC), cerebral (HCMEC) and adipose (HAMEC) microvascular as well as pulmonary artery (HPAEC) and coronary artery (HCAEC). Response to the TRPV4 agonist GSK1016790A was assessed by ratiometric Fura‐2 imaging of intracellular calcium concentration [Ca2+]i, measuring transendothelial electrical resistance (TEER), and fluorescence imaging of cytoskeletal actin and VE‐cadherin. TRPV4 protein expression was densitometrically quantified by Western blot, normalized to GAPDH for comparison between the five cell types.ResultsAgonist treatment increased [Ca2+]i and decreased TEER in all endothelial cell types studied, while vehicle (dimethylsulfoxide) had no effect. Interestingly, there was strong inverse correlation between the [Ca2+]i response and decrease in TEER amongst the three microvascular cell types, HPMEC, HAMEC and HCMEC, with the [Ca2+]i and reduction of TEER increasing in the order HPMEC < HAMEC < HCMEC. This effect was corroborated by fluorescence imaging that showed TRPV4 agonism caused intercellular adherens junctions to become disrupted and gaps to form within the endothelial monolayer. In some cases, endothelial cells significantly contracted and became rounded, losing surface VE‐cadherin and forming actin stress fibers. The degree of this effect varied between microvascular cells, again in the increasing order HPMEC < HAMEC < HCMEC. Furthermore, these observations correlated with quantification of Western blot showing HCMECs had highest expression of TRPV4 protein. Notably, while macrovascular HPAECs and HCAECs showed quantitatively similar responses as microvascular endothelial cells, they did not fit the linear regression between [Ca2+]i and TEER response.ConclusionThese results demonstrate quantitative heterogeneity in endothelial TRPV4 function in different vascular beds, and identify TRPV4 as a major regulator of microvascular endothelial cell permeability, while confirming the established differences in barrier function between micro‐ and macrovascular endothelial cells.Support or Funding InformationCanadian Institutes of Health Research (CIHR)Ontario Research Fund (ORF)