bluuebunny/crossref_metadata_2025_split huggingface dataset:
Muscle‐derived SDF‐1α/CXCL12 modulates endothelial cell proliferation but is not required for exercise training‐induced angiogenesis
Authors: Okutsu Mitsuharu , Yamada Mami , Hokazono Chihiro , Tokizawa Ken , Marui Shuri , Iwata Masahiro , Lira Vitor A , Suzuki Katsuhiko , Miura Shinji , Nagashima Kei 
Published: June 2021

Chronic elevations in contractile activity, as observed with exercise training, increase capillarity density in skeletal muscle. Here, we demonstrate that the stromal cell‐derived factor‐1 alpha (SDF‐1α/CXCL12) is the most abundantly expressed angiogenesis‐associated chemokine in capillary‐rich oxidative soleus and exercise‐trained plantaris muscles. CXCL12 is also increased in muscle‐specific peroxisome proliferator‐activated receptor γ coactivator 1α transgenic mice (PGC‐1α mTg) when compared to wild‐type littermates. Additionally, CXCL12 is increased in C2C12 myotubes by cyclic mechanical stretch. Furthermore, exposure of human umbilical vein endothelial cells (HUVEC) to conditioned medium from cyclically stretched C2C12 myotubes enhanced cell proliferation. Such an effect was specific to CXCL12 signaling because co‐treatment with AMD3100, an antagonist of the CXCL12 receptor CXCR4, disrupted the proliferative response. To gain further insight into a potential role for CXCL12 in modulating chronic contractile activity‐induced angiogenesis in vivo, we studied muscle‐specific CXCL12 knockout mice (CXCL12 mKO). Interestingly, our results demonstrate that these mice have normal baseline capillary density and preserved angiogenesis when exercise‐trained. These findings are consistent with a muscle‐derived CXCL12‐dependent modulatory role of endothelial cell proliferation in response to increased contractile activity. However, muscle‐derived CXCL12 is not required for exercise training‐induced angiogenesis in skeletal muscle.Support or Funding InformationThis study was supported by Grant‐in‐Aid for Challenging Exploratory Research (16K13019) and Grant‐in‐Aid for Scientific Research (B) (15H03080) (18H03153) to Mitsuharu Okutsu.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Peripheral Arterial Adaptations to All‐Extremity Aerobic Exercise Training in Type 2 Diabetes
Authors: Sakarya Yasemin , Hwang Chueh‐Lung , Lim Jisok , Kim Han‐Kyul , Yoo Jeung‐Ki , Handberg Eileen M. , Hwang Moon‐Hyon , Petersen John W. , Holmer Brady J. , Lapierre Stephanie S. , Christou Demetra D. 
Published: June 2021

Type 2 diabetes (T2D) is associated with arterial remodeling and dysfunction which increase the risk for cardiovascular disease (CVD). There is some evidence that aerobic exercise induces arterial adaptations in the exercising limbs, but not in the non‐exercising limbs, suggesting that all‐extremity exercise might be advantageous. However, the optimal exercise training regimen to induce peripheral arterial adaptations in individuals with T2D is unknown. Therefore, the purpose of this study was to compare, in T2D patients, the effects of all‐extremity high‐intensity interval training (HIIT) vs. moderate‐intensity continuous training (MICT) on arterial structure and function in the exercising arms and legs. Thirty‐three sedentary T2D patients (46 to 78 yrs of age; 64 ± 1 yrs; means ± SE), free of CVD, were randomized to HIIT (n = 12), MICT (n = 10), or non‐exercise control group (CONT; n = 11). HIIT and isocaloric MICT were performed on a non‐weight‐bearing all‐extremity ergometer (Airdyne, Schwinn), 4 days/week for 8 weeks under supervision. HIIT consisted of 4×4‐min bouts at 90% of peak heart rate (HRpeak) interspersed by 3‐min bouts at 70% of HRpeak, while MICT consisted of 32 min at 70% of HRpeak. Both HIIT and MICT were preceded by a 10‐min warm‐up and followed by a 5‐min cool‐down at 70% of HRpeak. Arterial diameter (ultrasonography), intima‐medial thickness (IMT; ultrasonography), blood flow (Doppler) and arterial compliance (change in diameter and change in pressure) were assessed at the brachial (arm) and common femoral (leg) arteries at pre‐ and post‐intervention. Following the 8‐week exercise intervention, brachial and femoral diameter, IMT, blood flow and compliance did not significantly change in response to HIIT or MICT (P≥0.1 for group × time interaction). In conclusion, 8 weeks of all‐extremity HIIT and MICT do not lead to arterial remodeling or changes in arterial function in the exercising arms and legs in patients with T2D.Support or Funding InformationThis work was supported by National Institute of Aging grant AG050203 to DDC.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Empagliflozin on Cardiac Function of Diabetic Infarcted Rats: Echocardiographic Evaluation
Authors: Silva Bruno Durante , de Souza Leandro Eziquiel , da Silva Maikon Barbosa , Soares Camila Molina , Cruz Paula Lázara , Dourado Paulo Magno Martins , Consolim‐Colombo Fernanda , Irigoyen Maria Cláudia Costa 
Published: June 2021

ObjectiveThe present study aims evaluating the protective effects of Empagliflozin on the cardiac function of diabetic Wistar rats submitted to acute myocardial infarction.Methods12 rats of the Ratus norvegicus specie, Wistar lineage, were anesthetized with isoflurane and submitted to induction of diabetes by the administration of 50 mg/kg streptozotocin in the caudal vein. Confirmation of hyperglycemia was performed on the 14th day after injection and the animals with glycemia equal to or greater than 250 mg/dL were considered diabetics. These animals were allocated in 3 groups: D (n = 4), ID (n = 4) and ITD (n = 4). The animals of the groups ID and ITD were anesthetized with ketamine (50 mg/kg) and xylazine (10 mg/kg) and then they were submitted to thoracotomy for ligature of the left coronary artery and received analgesia after the procedure (Tramadol chlorhydrate – 10 mg/kg). The animals of the group ITD received the 3 mg/kg dose of empagliflozin daily for 14 days through gavage. After this period, the animals were submitted to anesthesia (1% isoflurane) and then catheterized (vein and femoral artery) for evaluation of direct blood pressure and echocardiographic examination.ResultsDiabetes induction was confirmed by fasting hyperglycemia in the 3 groups. A Fractional Area Change (FAC) of 43.81%, 22.45% and 22.70% was observed in the D, ID and ITD groups, respectively (p = 0.00004), confirming the infarction in groups ID and ITD. The ITD group presented higher values of E′/A′ (D: 0.53; DI: 0.64; DIT: 2.01, p = 0.0022) and lower E/E′ values in comparison to D and ID groups (D: 16.99; ID: 19.39, ITD: 7.54, p = 0.0241). These parameters suggest a restoration of the diastolic function and a reduction of the ventricular filling pressure in animals treated with empagliflozin. There was also an improvement in the ejection fraction (EF) in the animals of the group ITD (25.40%) compared to the ID group (12.58%). There were no significant changes in the hemodynamic parameters evaluated, both in blood pressure (MAP: D: 105.96 mmHg, ID: 100.72 mmHg and ITD: 108.29 mmHg – p> 0,05) and in heart rate (HR: D: 303 bpm, ID: 300 bpm, ITD: 327 bpm – p> 0,05).ConclusionTreatment with Empagliflozin for 14 days was able to promote improvement of the cardiac function of infarcted diabetic rats.Support or Funding InformationThis study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ‐ Brasil (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Capsazepine decrease the pressor response to stimuli other than transient receptor potential vanilloid‐1 agonists
Authors: Ducrocq Guillaume P , Estrada Juan A , Kim Joyce S , Kaufman Marc P 
Published: June 2021

Capsaicin‐induced stimulation of Transient Receptor Potential Vanilloid‐1 (TRPV1) receptors on thin fiber muscle afferents reflexively increases arterial blood pressure in multiple species of mammals. In rats, blocking these receptors with capsazepine reduced the pressor response to contraction of the hindlimb muscles, a finding which suggests that TRPV1 receptors mediate the exercise pressor reflex. Capsazepine, however, has been shown in vitro to block voltage gated calcium channels, raising the possibility that it might have reduced the exercise pressor reflex by another mechanism. To test that alternative, we examined the effect of capsazepine on the pressor responses to intra‐arterial injection of bradykinin and diprotonated phosphate, metabolic by‐products of contraction believed to play a role in the elicitation of the exercise pressor reflex. In decerebrated Sprague‐Dawley rats, we injected bradykinin (1.5 μg/kg, 0.1 mL; n = 9) or diprotonated phosphate (86 mM, pH = 6.0, 0.2 mL; n = 3) into the arterial supply of the hindlimb before and after injecting capsazepine (100 μg/mL, 0.1 mL). We challenged the effectiveness of capsazepine to inhibit TRPV1 receptors by injecting the specific TRPV1 agonist, capsaicin (0.5 μg/kg, 0.1 mL). Capsazepine decreased the pressor response to capsaicin (50 ± 11 mmHg vs.32 ± 14 mmHg [mean ± SD]; p = 0.06, d = 1.03) and to bradykinin (25 ± 8 mmHg vs.13 ± 12 mmHg; p = 0.03, d = 0.85). The effect of capsazepine on the pressor response to diprotonated phosphate was unclear due to a small sample size (44 ± 25 mmHg vs. 31 ± 29 mmHg). Intra‐arterial injection of the vehicle for capsazepine had no effect on the pressor responses to bradykinin, diprotonated phosphate and capsaicin. Our data suggest that capsazepine is not a selective antagonist to TRPV1 receptors and should not be used to test the hypothesis that TRPV1 receptors on thin fiber afferents play a role in evoking the exercise pressor reflex.Support or Funding InformationSupported by NIH P01 HL 134609.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Prevention of Obesity‐Associated Coronary and Cardiac Diastolic Dysfunction by Deletion of Smooth Muscle Cell Mineralocorticoid Receptor in Females
Authors: Brown Scott M , Aragonez Christian G , Khan Maloree L , Chandrasekar Bysani , DeMarco Vincent G , Jaffe Iris Z , Bender Shawn B 
Published: June 2021

Coronary microvascular dysfunction is independently predictive of cardiac diastolic dysfunction and both conditions are common in obesity and associated metabolic syndrome. Recent work by us and others indicates that mineralocorticoid receptor (MR) antagonism treats obesity‐associated coronary and cardiac diastolic dysfunction. Vascular cell‐specific MR involvement in these obesity‐related defects remains unclear. Thus, we evaluated the hypothesis that deletion of smooth muscle cell (SMC) MR would prevent obesity‐associated coronary and cardiac diastolic dysfunction in females. Female wild‐type (WT) and SMC MR knockout (KO) mice were fed a standard chow or western diet (WD) to induce obesity for 16 weeks. WD feeding induced obesity, hyperinsulinemia, hypercholesterolemia, and visceral adipose inflammation in both WT and SMC MR KO mice. Assessment of coronary vascular function via wire myography revealed WD‐induced impairment of endothelium‐dependent vasodilation and enhanced vasoconstriction to the thromboxane A2 analog U46619 in WT but not SMC MR KO mice. Vasodilation to the nitric‐oxide donor sodium nitroprusside was unchanged by WD feeding. Global quantitative proteomics of aortas from each group revealed a number of differentially expressed proteins following WD feeding including upregulation of the oxidative stress‐related small GTPase Rac‐1 in WT but not SMC MR KO aortas. Accordingly, pretreatment of coronary arteries with the superoxide dismutase mimetic Tempol restored endothelium‐dependent vasodilation in WD‐fed WT mice with no effect in SMC MR KO vessels. Furthermore, WD feeding induced cardiac diastolic dysfunction assessed by echocardiography (i.e., increased E/E′, reduced E′/A′, increased diastolic stiffness). Coincident with prevention of WD‐induced coronary dysfunction, SMC MR deletion prevented WD‐induced cardiac diastolic dysfunction. Importantly, this cardioprotective effect of SMC MR deletion occurred independent of changes in left ventricular hypertrophy, blood pressure, aortic stiffening, and proteinuria. Taken together, our data demonstrate a central role of SMC MR signaling underlying WD‐induced coronary and cardiac diastolic dysfunction in females. Importantly, this study adds to an emerging body of evidence suggesting a vascular origin of cardiac dysfunction in obesity.Support or Funding InformationSupported by NIH (HL136386 to SBB, HL119290 to IZJ) and the Department of Veterans Affairs BLR&D (CDA‐2 IK2 BX002030). BC is supported by Department of Veterans Affairs (IK6 BX004016 and I01 BX002255).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Coronary Smooth Muscle Cytodifferentiation is Associated with an Increase in Pro‐Inflammatory, Pro‐Calcifying Gene Expression in an Organ Culture Model of Coronary Artery Disease
Authors: Badin Jill , Sturek Michael 
Published: June 2021

IntroductionDuring coronary artery disease (CAD) progression, coronary smooth muscle (CSM) cells dedifferentiate into synthetic or osteogenic phenotypes that induce CSM proliferation and vascular calcification, respectively. This phenotypic switching is in parallel to the upregulation of intracellular [Ca2+]i handling observed in early CAD and downregulation observed in late CAD. These [Ca2+]i handling alterations may play a role in promoting coronary artery calcification (CAC), which is associated with increased risk of cardiovascular health complications and mortality. Therefore, the aims of this study are two‐fold: 1) utilize an in vitro organ culture model of CAD to elucidate the extent of CSM phenotypic switching and 2) identify what genes are upregulated in each major CSM phenotype. Collectively, the data show possible signaling mechanisms and cellular processes that contribute to CAD pathophysiology, specifically CAC.MethodsCoronary rings from lean Ossabaw miniature swine were either used fresh or cultured in osteogenic media containing 10% FBS, 180 mg/dL glucose, 1% penicillin/streptomycin, 3.8 mM inorganic phosphate, and 7.5 U/mL alkaline phosphatase in DMEM for 3 days. To identify cells, cell population heterogeneity, and gene expression, CSM were enzymatically dispersed and used for single‐cell RNA‐sequencing.ResultsThe presence of differentiated, contractile CSM phenotypic markers including actin (ACTA2), myosin light chain (MYL9), myosin heavy chain (MYH11), and calponin (CNN1) were drastically reduced in the transcriptome of cells in cultured arterial rings. CSM from cultured rings also exhibited higher levels of transforming growth factor beta 1 (TGFB1) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin (SMARCA4), both markers of the synthetic, proliferative phenotype. Furthermore, genes related to inflammation, chemotaxis, oxidative stress, extracellular matrix degradation, and vascular calcification were upregulated in CSM from cultured arterial rings when compared to CSM from fresh, noncultured rings.ConclusionAfter 3 days cultured in osteogenic media, CSM in whole arterial rings undergo dedifferentiation, as evidenced by decreased contractile markers and increased proliferative markers. This is associated with the upregulation of several genes associated with CAD pathophysiology, including genes involved in inflammation, calcification, and oxidative stress. This study will further help to parse out the complex cellular mechanisms involved in the progression of CAD and CAC.Support or Funding InformationThis work was supported by the CorVus Biomedical Research Fund.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
CK2 Phosphorylation of ENaC Directs Ankyrin‐3 Activity
Authors: Berman Jonathan Max , Mironova Elena , Stockand James , Archer Crystal 
Published: June 2021

The Epithelial Na+ Channel, ENaC, is the final arbiter of sodium excretion in the kidneys. As such, discretionary control of ENaC by hormones is critical to the fine‐tuning of electrolyte and water excretion and consequently, blood pressure. We recently showed that phosphorylation of ENaC by CK2 in a putative ANK3 binding domain regulates ENaC activity. Therefore we tested the necessity and sufficiency of ANK3 for normal ENaC function. We produced tissue specific ANK3 knockout mice in the aldosterone sensitive distal nephron. Knockout was verified by immunohistochemistry. Split open tubule recordings from these mice showed significantly decreased baseline ENaC activity. The mice displayed a insensitivity to the specific CK2 inhibitor TBB, a casein‐kinase II inhibitor compared to control. Together these results suggest that ANK3 modulates ENaC activity by interacting with CK2 phosphorylation sites in Beta and Gamma ENaC. In future work we will examine the mechanism by which this interaction modifies ENaC activity.Support or Funding InformationThis research was supported by American Heart Association Grants 15GRNT‐22930030 and 17GR‐NT‐3292002 (to J. D. Stockand) and 17POST33660468 (to J. M. Berman) and by National Institutes of Health Grants T32‐HL‐00744536A1 (to J. D. Stockand and J. M. Berman), K12GM111726 (to J. M. Berman), and F32‐DK‐104572 (to E. Mironova).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
RNA Seq Analysis Reveals Metabolic and Natriuretic Pathways Regulated by Renal T Cell Infiltration
Authors: Dayton Alex , Yang Chun , Alsheikh Ammar , Abais‐Battad Justine , Bukowy John , Pan Xiaoqing , Mattson David , Cowley Allen , Evans Louise 
Published: June 2021

Previously, we presented work using a servo‐control system to maintain pressure to the left kidney at normotensive levels during high salt feeding. Using this approach we have demonstrated that T‐cell infiltration into the kidney during salt‐induced hypertension is a direct consequence of pressure. Further, we used RNA sequence data to detect transcriptional pathways that differ between hypertensive and normotensive kidneys, including several pathways related to immune cell migration and activation.In order to further study the interactions between T‐cells and salt‐sensitive hypertension in the Dahl S rat, we use a CD247−/− strain, which lack functional T‐cells. These rats demonstrate reduced pressures relative to wild‐type (WT) rats when fed high salt. Here, we present a study in which we adapted the servo‐control method so that the renal perfusion pressure to the left kidney of WT rats was matched on a daily basis to that of the left kidney of CD247−/− rats. This results in exposure of the left kidneys to an equivalent hypertensive response to salt. Analysis of these “pressure‐matched” kidneys therefore controls for the potentially confounding effects of pressure, and allows for a more direct comparison of tissues to reveal the effects of renal T‐cell infiltration in hypertension.Both CD247−/− and WT rats (N=4) were instrumented for servo‐control, as described previously. These rats were then fed a 4% NaCl diet to induce hypertension. Using the servo‐control system, the left kidney of the WT rats was maintained on a daily basis to match the blood pressures exhibited by the CD247−/− rats. At the conclusion of 12 days, the rat's kidneys were flushed with saline, followed by isolation of the renal medulla for RNA‐seq analysis.RNA was reverse transcribed and then sequenced on an Illumina Hi‐Seq 2500 sequencer. Data was then aligned to the RN6 genome and quantified. 2865 transcripts were found to be significantly different between the CD247−/− and WT medullas (p < 0.05). Overrepresentation analysis using DAVID found significant differences in transcripts belonging to oxidative phosphorylation (p < 8.1 * 10−22), TCA cycle (p < 5.0 * 10 −9), collecting duct acid secretion (p < 5.7 * 10 −4) and aldosterone‐regulated sodium reabsorption (p < 0.013) pathways, among others. This analysis suggests that these pathways are regulated by T‐cell infiltration and activation within the renal medulla. These pathways are viable targets for the further study of the effect of immune cells on blood pressure.Support or Funding InformationNIH F30HL127979 AHA 17SDG33660574This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Single Cell Ablation in the Zebrafish Kidney using SPIM and a Bessel Beam
Authors: Brown Cara , Buckley Charlotte , Hoffmann Scott , Rider Sebastien , Girkin John , Mullins John 
Published: June 2021

Selective plane illumination microscopy (SPIM) uses low‐powered laser light to rapidly and precisely capture high‐resolution images of cells within live organisms, revealing fine details of the cell structure. By combining a bespoke SPIM/Bessel beam in combination with appropriate fluorescent cell‐specific reporters, individual cells can be located and targeted for ablation via apoptosis.Incorporation of fluorescent reporters such as LifeAct‐red fluorescent protein (RFP) or the photosensitizing protein, KillerRed (KR), into the genome of the optically clear zebrafish larvae, allows specifically labelled cells to be visualized and/or optically ablated deep within developing organs and in real‐time. We have used this technology to visualize and target a) cells of the renin lineage (CoRLs)1 and b) podocytes, within the live Zebrafish kidney. Transgenic fish expressing KR under the control of the renin and podocin promoters were established and used independently for imaging/ablation experiments. Using a Bessel beam in combination with SPIM to precisely activate KR allows relatively low laser power to be employed resulting in 100% viability of the fish following laser treatment. Low energy laser ablation allows the cell injury/ablation to be imaged and assessed over an extensive time period (hours).Support or Funding InformationBHF Center of Research Excellence Award; Kidney Research UK award; EPSRC/MRC DT (Optima) AwardThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.