bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antagonism between PKA and Epac signaling is involved in the regulation of PGE2‐induced ICAM‐1 expression in bEnd.3 cells
Authors: Park Tae Yeop , Lee Kwang Min , Kim Jae Mi , Jung Yi-Sook , Baik Eun Joo , Moon Chang-Hyun , Lee Soo Hwan 
Published: June 2021

Increased leukocyte adhesion and infiltration under various pathological conditions is accompanied by increased expression of endothelial ICAM‐1 and the blockade of ICAM‐1 ligation limits leukocyte infiltration and brain damage. PGE2 is known to be the principal pro‐inflammatory prostanoid and play important roles in brain diseases through binding to EP1‐4 receptors. However, there have been contradictory reports on its actions during inflammation processes, especially in vascular endothelial cells. In this study, we investigated the roles of PGE2 in the expression of ICAM‐1 in bEnd.3 cells and therein involved signaling pathways. We investigated that elevation of cAMP is necessary for PGE2‐induced ICAM‐1 expression in bEnd.3 cells. We determined effect of PGE2 on Epac activation using Rap1‐GTP pull down assay and effect of Epac on PI3K/Akt activation as well as ICAM‐1 expression. Next, we showed that loss of Akt activity results in inhibition of PGE2‐induced NF‐κB activation. On the other hand, interestingly enough, PKA inhibitor stimulated Akt phosphorylation and ICAM‐1 expression and specific activator inhibited PGE2‐induced ICAM‐1 expression and Akt phosphorylation. Taken together, these data suggest that this antagonism between PKA and Epac signaling is importantly involved in the regulation of PI3K/Akt signaling axis, and thereby ICAM‐1 expression in cerebrovascular endothelial cells.This study was supported by grants from Ajou University School of Medicine and Gyunggi‐do through CCRB‐GRRC
Temporal relationship between inflammation‐induced lymphangiogenesis and angiogenesis in rat mesenteric microvascular networks
Authors: Sweat Richard Shelton , Stapor Peter Conrad , Murfee Walter Lee 
Published: June 2021

The interrelationship between lymphangiogenesis and angiogenesis remains under‐investigated. The objective of this study was to compare the temporal dynamics of lymphatic and blood vessel growth post inflammatory stimulus in the rat mesentery. Mesenteric tissues were harvested from unstimulated adult male Wistar rats and at 3 and 10 days post compound 48/80 stimulation (n=4 animals, 7 tissues per group). Tissues were labeled with antibodies to PECAM, LYVE‐1, and class III β‐tubulin. Angiogenesis was confirmed by increased vascular area per tissue area at 10 days. Blood capillary sprouting increased at day 3 and remained elevated at day 10. Over the 10 day time course, lymphatic vascular area remained comparable. Lymphatic sprouting increased at day 3 and continued to increase through day 10. The peak in lymphatic sprouting correlated with the presence of class III β‐tubulin positive endothelial cells along lymphatic blind ended vessels. Our results establish 48/80 stimulation as a model of lymphangiogenesis in the rat mesentery. While lymphangiogenesis occurs in concert with angiogenesis, the peak in lymphatic sprouting apparently lags blood capillary sprouting. Class III β‐tubulin upregulation during the peak of lymphatic sprouting implicates it as a novel marker of lymphangiogenesis. Supported by the Board of Regents of the State of Louisiana LEQSF(2009‐12)‐RD‐A‐19.Grant Funding Source : Board of Regents of the State of Louisiana LEQSF(2009‐12)‐RD‐A‐19
Interplay between NO, prostaglandins and KATP channels in the lymphatic pumping dysfunction observed during experimental intestinal inflammation
Authors: von der Weid Pierre-Yves , Mathias Ryan , Rehal Sonia 
Published: June 2021

Lymphatic vessels rhythmically contract to actively propel lymph. This function, critical to tissue fluid homeostasis and immune cell trafficking is impaired in Crohn's disease and in the guinea‐pig model of TNBS ileitis, suggesting compromised lymph flow and lymphatic vessels potential players in the disease. Nitric oxide (NO) and prostaglandins (PGs), abundantly produced during intestinal inflammation, are known to activate ATP‐sensitive potassium (KATP) channels expressed in lymphatic muscle. Our aim was to assess the role of KATP channels, NO and PGs in inflammation‐induced lymphatic pumping dysfunction.After induction of intestinal inflammation, mesenteric lymphatics were collected for qPCR analysis, or isolated to assess their contractile and electrophysiological properties.Expression of mRNA for KATP channel subunits Kir6.1 and SUR2B, nitric oxide synthase iNOS and cyclooxygenase COX2 was significantly upregulated in lymphatics from TNBS‐compared to sham‐treated animals. Vessels from TNBS‐treated animals were dilated, quiescent, with strongly hyperpolarized muscle. Administration of the KATP blocker glibenclamide, iNOS inhibitor 1400W and COX inhibitor indomethacin restored pumping and depolarized lymphatic muscle.Our findings suggest that NO and PGs mediate lymphatic contractile dysfunction seen in TNBS‐treated animals via KATP channel opening.Supported by CIHR
Diabetic genetic background does not influence the isoflurane preconditioning in human cardiomyocytes differentiated from induced pluripotent stem cells derived from a type 1 diabetes patient
Authors: Kikuchi Chika , Canfield Scott , Bai Xiaowen , Koopmeiners Andrew , Kwok Wai-Meng , Schaefer Richard , Bosnjak Zeljko 
Published: June 2021

Anesthetic preconditioning (APC) has been proved to increase myocardial tolerance to ischemia reperfusion injury. However, growing evidence shows that APC is attenuated in diabetes. The generation of induced pluripotent stem cells (iPSCs) enabled the production of patient specific cardiomyocytes (CMs), providing a novel model to study the roles of diabetic genetic background and environmental factors in the attenuation of APC. iPSCs generated from a healthy donor and a T1DM patient were directly differentiated into CMs (N‐iPSC‐CMs and T1DM‐iPSC‐CMs, respectively). The differentiated CMs were confirmed by the expression of CM‐specific markers troponin T and sarcomeric á‐actinin and the presence of action potentials. Lactate dehydrogenase (LDH) release assay was then performed to determine the viability with or without isoflurane preconditioning in response to oxidative stress. The isoflurane preconditioning decreased LDH release in both N‐iPSC‐CMs and T1DM‐iPSC‐CMs in response to oxidative stress.iPSCs generated from both the healthy donor and the T1DM patient can differentiate into functional cardiomyocytes. Importantly, our results show that isoflurane can precondition both N‐iPSC‐CMs and T1DM‐iPSC‐CMs, suggesting that genetic factors may not play major roles in the attenuation of APC. P01GM066730 and R01HL034708 from the NIH, Bethesda, MD (to Z. Bosnjak).
Imaging of Single Fluorescent Cells for 3‐D Quantification of Neovascularization in Ischemic Myocardial Tissue
Authors: Hakimzadeh Nazanin , van Horssen Pepijn , van den Wijngaard Jeroen PHM , Piek Jan J , Spaan Jos AE , Verberne Hein J , Siebes Maria 
Published: June 2021

By employing high‐resolution three‐dimensional (3D) imaging, we aim to detect and quantify monocytes targeting active sites of neovascularization in ischemic myocardium. As a first step, distinguishing exogenously administered cells from highly autofluorescent myocardial tissue and vascular casting material must be addressed. The aim of this study was to optimize visualization of single fluorescent cells with an imaging cryomicrotome.Human vascular endothelial cells (HUVECs) labeled with CellTrackerTM Orange CMTMR (5, 10, 25 and 72μM) were infused into postmortem coronary arteries of rat and rabbit hearts together with replica resin (Mercox) containing fluorescent dye (Potomac Yellow or UV Blue). Following polymerization of replica resin, hearts were frozen at −20ºC and further processed with the imaging cryomicrotome.In 3D reconstructions of hearts cut at 5μm slice thickness, HUVECs labeled with dye concentrations higher than 5μM were visible in the presence of UV Blue cast material, while cells labeled with 72μM dye demonstrated superior brightness.The successful identification of single exogenously administered cells in the presence of vascular cast material will allow quantification of actively growing collaterals which recruit monocytes in ischemic myocardial tissue.Supported by the Center for Translational Molecular Medicine (EMINENCE) and the Netherlands Heart Foundation
Effects of Fresh and Aged Vehicular Particulate Emissions on Blood Pressure in Normal Adult Male Rats
Authors: Lamoureux Denise Paige , Diaz Edgar A , Coull Brent A , Papapostolou Vasileios , Lawrence Joy , Sato Rodrigo , Godleski John J 
Published: June 2021

BACKGROUNDAssociations between exposure to fine particulate matter (PM2.5) and blood pressure (BP) have been inconsistent in epidemiologic studies.OBJECTIVESWe used a unique exposure system to separate traffic‐derived PM2.5 into primary and secondary components to measure effects on BP.METHODSSprague Dawley rats were repeatedly exposed to primary only (P), secondary organic aerosol only (SOA), a combination of the two (P+SOA) or filtered air for 5‐hours/day for 3 weeks. Exposure dose was ~50 μg/m3. BP was measured continuously using implanted telemetry. Mixed effects models were used to compare responses of systolic (SBP), diastolic blood pressure (DBP) and heart rate (HR).RESULTSExposure to P increased and maintained an effect on SBP and DBP across weeks showing a significant dose response. SOA exposure on the first day resulted in a significant increase in both SBP and DBP (p=.001, p=.0003) becoming strongly negative by week 3. With P+SOA, significant increases in SBP and DBP of 13 mmHg were observed on the first day of exposure (p=.04, p=.0015) which was maintained through week 1 for SBP and through week 2 for DBP. Sham exposures in the SOA and P+SOA groups after 3 weeks showed compensatory decreases in both SBP and DBP. No exposure had a significant effect on HR.CONCLUSIONSBoth primary and secondary traffic derived aerosols can substantially increase SBP and DBP but these increases are eventually lost.
Impaired Baroreflex Sensitivity in Anabolic Steroid Users
Authors: dos Santos Marcelo Rodrigues , Porello Rafael Armani , Sayegh Ana L C , Hong Valeria , Toschi-Dias Edgar , Bortolotto Luiz A , Yonamine Mauricio , Negrao Carlos E , Alves Maria-Janieire N N 
Published: June 2021

PurposeExacerbated sympathetic nerve activity and increased blood pressure have been documented in anabolic androgenic steroid users (AASU). We tested the hypothesis that arterial baroreflex sensitivity (BRS) and carotid distensibility would be reduced in AASU.MethodsTen AASU and 10 age‐paired anabolic androgenic steroid nonusers (AASNU) were studied. Both groups were involved in strength training (90% 1MR) and AASU were self‐administered anabolic steroids for at least 2 years. The use of AAS was proved by urine. Heart rate (HR) was evaluated by EKG and blood pressure non‐invasively on a beat to beat. BRS was analyzed by time domain through spontaneous fluctuations between systolic blood pressure (SBP) and HR. Carotid artery distensibility was measured by doppler (M‐mode).ResultsHR was higher in AASU compared to AASNU (69±3 vs. 59±3 bpm, P≤0.05). Systolic (123±4 vs. 118±2 mmHg, P=0.29), diastolic (72±2 vs. 67±2 mmHg, P=0.12) and mean blood pressure (90±3 vs. 85±2 mmHg, P=0.15) were not different between groups. BRS for increases (14.2±2 vs. 22.8±3 msec/mmHg, P=0.05) and decreases (13.3±1 vs. 19.2±2 msec/mmHg, P=0.04) were lower in AASU. Carotid distensibility was reduced in AASU (7±1 vs. 9±1 %, P≤0.05).ConclusionImpaired BRS and reduced carotid distensibility may prematurely lead to increased cardiovascular risk in AASU.
Baroreflex sensitivity is associated with blood pressure transients in young men but not young women
Authors: Matzek Luke J , Hart Emma C , Charkoudian Nisha , Joyner Michael J , Curry Timothy B , Barnes Jill N 
Published: June 2021

Baroreflex sensitivity is calculated from the slope of the relationship between blood pressure and muscle sympathetic nerve activity (MSNA) or cardiac R‐R interval. The magnitude of decrease in blood pressure during a vasoactive drug bolus (i.e. modified Oxford) to test the baroreflex may be associated with the calculated baroreflex sensitivity (BRS) slope. We investigated whether the cardiac or sympathetic BRS are associated with the acute decrease in blood pressure during a modified Oxford in young healthy men and women. Forty‐five women (27 ± 1 yrs, BMI 22.9 ± 0.3 kg/m2) and 30 men (27 ± 1 yrs, 24.2 ± 0.4 kg/m2) were studied. MSNA was measured via peroneal microneurography and blood pressure was measured with a brachial intraarterial catheter. Women and men had similar mean arterial pressures (91 ± 1 vs. 90 ± 1 mmHg), cardiac BRS (19 ± 1 vs. 21 ± 2 ms/mmHg), and sympathetic BRS (−6 ± 0.4 vs. −7 ± 0.6 AU/beat/mmHg), respectively. The decrease in systolic blood pressure (SBP) and pulse pressure (PP) was positively related to cardiac BRS in men (r=.47; p<0.01; r=.49; p<0.01). However, there was no relationship between the decrease in blood pressure and sympathetic BRS in men. In addition, there was no association between any blood pressure transients with either cardiac or sympathetic BRS in women. Our results suggest the magnitude of decrease in blood pressure is associated with cardiac BRS in men, but not women.Funded by NIH
Subarachnoid hemorrhage (SAH)‐linked brain inflammation contributes to arteriolar dilating dysfunction and neuropathology in rats
Authors: Xu Hao-liang , Paisansathan Chanannait , Vetri Francesco , Pelligrino Dale 
Published: June 2021

Brain injury and death arising from SAH remains a substantial clinical problem. In the present study, rats were subjected to SAH, via suture perforation of the anterior cerebral artery. In pilot experiments, we detected marked elevations in CSF expression of the astrocytic protein, S100B, at 48h post‐SAH. Since S100B is a ligand for the pro‐inflammatory receptor, RAGE (the receptor for advanced glycation end products), we tested the hypothesis that brain inflammation leads to impairment of arteriolar dilating function and contributes to brain damage. In rats prepared with closed cranial windows at 1–3 days post‐SAH, pial arteriolar dilation assessments were performed using intravital microscopy/videometry. To evaluate the role of S100B and RAGE, rats were given the following treatments at 30 min post SAH: (1) ONO 2506 (10 mg/kg, ip), a novel S100B inhibitor; or (2) sRAGE (icv via osmotic pump), a soluble RAGE decoy. After SAH, we observed diminished pial arteriolar responses to hypercapnia, and topically‐applied adenosine, acetylcholine, and S‐nitroso‐N‐acetyl penicillamine, with maximum attenuation seen at 48 h post SAH. The applications of both ONO 2506 and sRAGE significantly prevented the impaired pial arteriolar dilating responses. Neuropathology at 48h post‐SAH was evaluated using FluoroJade B (FJB) staining, which detects damaged neurons. The high level FJB reactivity seen in the ipsilateral cortex, hippocampus, and striatum in vehicle controls was markedly diminished in ONO 2506‐ and sRAGE‐treated rats. Collectively, these results indicate that, the activation of the S100B/RAGE – related proinflammatory pathway plays an important role in SAH‐associated cerebral vascular dysfunction. Blockade of the enhanced S100B and RAGE interaction may provide a promising treatment against SAH‐associated brain damage.Support: NS63279; HL88259
Acute Effects of Conjugate Equine Estrogen and Selective Estrogen Receptor‐α Agonist PPT on Postischemic Pial Arteriole Response in Rats
Authors: Zeynalov Emil , Ma Li , Rezvani Niloofar , Littleton-Kearney Marguerite T 
Published: June 2021

Study ObjectiveWe explored the effects of acute administration of conjugated equine estrogens (CEE), on postischemic pial arteriole dilatory capacity. Additionally, we determined determined if the beneficial effects of estrogen are mediated through estrogen receptor‐α (ER‐α) using the specific a specific agonist, propyl pyrazole triol (PPT).MethodsOvariectomized (OVX) female or male rats were anesthetized, and after placement of a closed cranial window over the parietal cortex, rats were subjected to 15‐min reversible forebrain ischemia, followed by 2 hr. reperfusion. OVX rats received intravenous CEE (1 mg/kg) or vehicle at the onset of reperfusion. Separate cohorts of OVX female or male rats were treated with the ER‐α agonist PPT intraperitoneally (2 mg/kg) 3 hours prior to ischemia. Pial artery dilatory capacity was tested before and after ischemia.ResultsAdministration of CEE improved vasodilatory response from −1.7 ± 4.43% to 15.31± 6.63% (p=0.0002). PPT augmented postischemic vasodilatory response in females from −2.63 ± 1.42% to 23.57 ± 11.3% (p= 0.005), and in male rats from −0.38 ± 2.88% to 30.84 ± 11.66% (p=0.007).ConclusionAcute administration of CEE or PPT restores postischemic pial arteriole vasodilatory reactivity to Ach. These findings suggest that the effects acute estrogen treatment after ischemic cerebral injury may be modulated via ER‐α.
Cerebral Vascular Blood Flow Changes During ‘Brain Freeze’
Authors: Blatt Melissa Mary , Falvo Michael , Jasien Jessica , Deegan Brian , Laighin Gearóid Ó , Serrador Jorge 
Published: June 2021

‘Brain freeze’ commonly occurs when ice cold food or liquid is rapidly consumed. It's mechanism remains unclear, however rapid cooling of the brain through the upper palate may cause local cerebral blood flow changes. The purpose of this study was to examine whether ‘brain freeze’ induces the hypothesized cerebrovascular changes.Using transcranial Doppler, we evaluated cerebral blood flow velocity (CBFV) in the middle (MCA) and anterior (ACA) cerebral arteries in 13 healthy adults while consuming ice and ambient water. Subjects drank ice water through a straw against the palate until pain developed. CBFV, heart rate, and blood pressure were analyzed, before pain, during pain and after pain.Consumption of ice water produced a tendency towards increased cerebral flow velocity in the ACA (P=0.078) but not the MCA (P=0.24). Ice water also resulted in greater cerebrovascular resistance during the experimentally induced “brain freeze” when compared to following ambient water consumption.Our results support a vascular mechanism for brain freeze. Ice water consumption resulted in a significantly greater cerebrovascular resistance as compared to that during ambient water consumption. However, the fact that cerebral flow increased during pain along with increases in blood pressure may suggest autoregulation was not as effective. Supported by NASA and NIH.
SUR2a gene is upregulated in skeletal muscle insulin resistance of obese rats: possible correlation with GLUT4 gene
Authors: Marques Milano Felipe dos Santos Ferreira , Mori Rosana Cristina Tieko , Okamoto Maristela Mitiko , Machado Ubiratan Fabres 
Published: June 2021

ObjectiveThe aim of this study was to investigate whether SUR2A (sulfonylurea receptor type 2A, ABCC9) MEF2a (myocyte enhancer factor‐2a) and HIF1a (Hypoxia‐inducible factor‐1) can influence glucose uptake in oxidative muscle soleus by regulating GLUT4 expression.MethodsInsulin resistance was induced in male Wistar rats by inducing obesity with monosodium glutamate (MSG). At the age 3 months, half control and MSG‐treated animals started receiving 0.1 mg/kg/day of glimepiride in the drinking water, and distributed in 3 experimental groups: control rats (C), MSG‐obese rats (O) and MSG‐obese rats treated with glimepiride (OG). Animals were submitted to insulin tolerance test (ITT) and samples of soleus muscle were excised for quantification of gene expression by Real Time RT‐PCR and GLUT4 protein.ResultsOG rats presented a 51% increase in SUR2A mRNA content in comparison to O and C rats (p<0.001). O rats showed 16% increase in GLUT4 mRNA content (p<0.01 vs. C), without any increase in GLUT4 protein. After glimepiride treatment, OG rats increased GLUT4 mRNA (21%, p<0.01 vs. C) and protein (131%, p<0.01 vs. C; and 73%, p<0.05 vs. O). No significant differences (p>0.05) in mRNA expression of MEF2a and HIF1a were found.ConclusionWe conclude that the glimepiride increased the GLUT4 expression in soleus of the insulin resistant animals which could be associated to SUR2A genes expression.
Myostatin Deletion Improves Insulin Resistance and Vascular Function in Obese Mice
Authors: Qiu Shuiqing , Mintz James , Salet Christina , de Chantemele Eric Belin , Stepp David W 
Published: June 2021

Insulin resistance in tissues such as muscle and fat is an underlying cause of obesity‐induced vascular dysfunction. Myostatin, secreted by skeletal muscle, has been associated with muscle metabolism and lowering myostatin may improve insulin sensitivity.HypothesisIncreasing muscle mass via myostatin deletion in obesity improves whole‐body metabolism and vascular function. A dual knockout (KO) approach was used including dual heterozygous lean mice, lean myostatin KO, db/db and db/db mice with and without myostatin KO. Myostatin KO increased gastrocnemius and gluteal muscle mass (37–52% in lean mice, 83% in obese mice). Myostatin KO improved HbA1c (6.33±0.50 vs. 10.00±1.54) in db/db mice, and fasting glucose in both lean and db/db mice, while myostatin KO had no effect on lipid metabolism. Glucose tolerance test results showed that db/db mice were insulin resistant and that myostatin KO improved insulin sensitivity in db/db mice. Obese db/db mice demonstrated an impaired microvascular vasodilation to acetylcholine that was improved by KO of myostatin. Adrenergic constriction was similar in all groups. Improvement of vasodilator capacity by myostatin KO was not attributed to vascular sensitivity to nitric oxide or changes in vascular structure and mechanics. Taken together, these data suggested that myostatin deletion in obese mice improved insulin resistance and endothelium dependent vasodilation.
Regulation of Nox4 by Calcineurin in the Diabetic Kidney
Authors: Williams Clintoria R. , Reddy Ramesh N. , Gooch Jennifer L. 
Published: June 2021

Diabetic nephropathy is a leading cause of morbidity and mortality and is due to the detrimental effects of hyperglycemia. Hypertrophy, an early response to hyperglycemia, may contribute to pathological changes in the kidney. Previously, we found that calcineurin (Cnβ) is required for diabetic hypertrophy. Other groups have reported a role for the Nox4 isoform of NADPH oxidase in diabetic nephropathy. Therefore, we examined if Cnβ and Nox4 act in a common pathway to induce hypertrophy in vitro and in vivo. First, we examined the effect of high glucose (HG) on Nox4 expression in primary kidney tubule epithelial cells (TECs). In wild‐type (WT) TECs, HG stimulated up‐regulation of Nox4 mRNA and protein expression. In contrast, HG failed to induce mRNA and Nox4 protein expression in Cnβ−/− TECs. Next, we examined regulation of Nox4 expression by hyperglycemia in vivo using WT and Cnβ−/− mice. In diabetic WT mice, whole kidney hypertrophy was induced and Nox4 expression was increased in the kidney cortex compared to control WT mice. In contrast, kidney hypertrophy was reduced in diabetic Cnβ−/− mice. Likewise, Nox4 expression was not increased in the kidney cortex of diabetic Cnβ−/− mice. These data show that Cnβ is required for HG‐mediated Nox4 up‐regulation in vitro and in vivo and establish Cnβ as a new player in Nox4 regulation in the diabetic kidney.Funding: VA MERIT and PECASE (JLG), NIDDK T32‐DK00756 (CRW)