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Thymosin beta4: a key factor for protective effects of eEPCs in acute and chronic ischemia.
Hinkel R, Bock-Marquette I, Hatzopoulos AK, Hazopoulos AK, Kupatt C
(2010) Ann N Y Acad Sci 1194: 105-11
MeSH Terms: Animals, Capillaries, Embryonic Stem Cells, Heart, Hindlimb, Ischemia, Myocardial Ischemia, Myocardium, Myocytes, Cardiac, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Rabbits, Swine, Thymosin
Show Abstract · Added November 18, 2010
Acute myocardial infarction is still one of the leading causes of death in the industrial nations. Even after successful revascularization, myocardial ischemia results in a loss of cardiomyocytes and scar formation. Embryonic EPCs (eEPCs), retroinfused into the ischemic region of the pig heart, provided rapid paracrine benefit to acute and chronic ischemia in a PI-3K/Akt-dependent manner. In a model of acute myocardial ischemia, infarct size and loss of regional myocardial function decreased after eEPC application, unless cell pre-treatment with thymosin beta4 shRNA was performed. Thymosin beta4 peptide retroinfusion mimicked the eEPC-derived improvement of infarct size and myocardial function. In chronic ischemia (rabbit model), eEPCs retroinfused into the ischemic hindlimb enhanced capillary density, collateral growth, and perfusion. Therapeutic neovascularization was absent when thymosin beta4 shRNA was introduced into eEPCs before application. In conclusion, eEPCs are capable of acute and chronic ischemia protection in a thymosin beta4 dependent manner.
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14 MeSH Terms
Increased seizure severity and seizure-related death in mice lacking HCN1 channels.
Santoro B, Lee JY, Englot DJ, Gildersleeve S, Piskorowski RA, Siegelbaum SA, Winawer MR, Blumenfeld H
(2010) Epilepsia 51: 1624-7
MeSH Terms: Animals, Cyclic Nucleotide-Gated Cation Channels, Disease Models, Animal, Hindlimb, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Kindling, Neurologic, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscarinic Agonists, Pilocarpine, Potassium Channels, Seizures, Severity of Illness Index
Show Abstract · Added August 12, 2016
Persistent down-regulation in the expression of the hyperpolarization-activated HCN1 cation channel, a key determinant of intrinsic neuronal excitability, has been observed in febrile seizure, temporal lobe epilepsy, and generalized epilepsy animal models, as well as in patients with epilepsy. However, the role and importance of HCN1 down-regulation for seizure activity is unclear. To address this question we determined the susceptibility of mice with either a general or forebrain-restricted deletion of HCN1 to limbic seizure induction by amygdala kindling or pilocarpine administration. Loss of HCN1 expression in both mouse lines is associated with higher seizure severity and higher seizure-related mortality, independent of the seizure-induction method used. Therefore, down-regulation of HCN1 associated with human epilepsy and rodent models may be a contributing factor in seizure behavior.
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14 MeSH Terms
Sustained VEGF delivery via PLGA nanoparticles promotes vascular growth.
Golub JS, Kim YT, Duvall CL, Bellamkonda RV, Gupta D, Lin AS, Weiss D, Robert Taylor W, Guldberg RE
(2010) Am J Physiol Heart Circ Physiol 298: H1959-65
MeSH Terms: Animals, Aorta, Biocompatible Materials, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Delivery Systems, Femoral Artery, Hindlimb, Ischemia, Lactic Acid, Male, Mice, Mice, Inbred C57BL, Nanoparticles, Neovascularization, Physiologic, Polyglycolic Acid, Polylactic Acid-Polyglycolic Acid Copolymer, Tomography, X-Ray Computed, Vascular Endothelial Growth Factor A
Show Abstract · Added March 14, 2018
Technologies to increase tissue vascularity are critically important to the fields of tissue engineering and cardiovascular medicine. Currently, limited technologies exist to encourage angiogenesis and arteriogenesis in a controlled manner. In the present study, we describe an injectable controlled release system consisting of VEGF encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). The majority of VEGF was released gradually over 2-4 days from the NPs as determined by an ELISA release kinetics experiment. An in vitro aortic ring bioassay was used to verify the bioactivity of VEGF-NPs compared with empty NPs and no treatment. A mouse femoral artery ischemia model was then used to measure revascularization in VEGF-NP-treated limbs compared with limbs treated with naked VEGF and saline. 129/Sv mice were anesthetized with isoflurane, and a region of the common femoral artery and vein was ligated and excised. Mice were then injected with VEGF-NPs, naked VEGF, or saline. After 4 days, three-dimensional microcomputed tomography angiography was used to quantify vessel growth and morphology. Mice that received VEGF-NP treatment showed a significant increase in total vessel volume and vessel connectivity compared with 5 microg VEGF, 2.5 microg VEGF, and saline treatment (all P < 0.001). When the yield of the fabrication process was taken into account, VEGF-NPs were over an order of magnitude more potent than naked VEGF in increasing blood vessel volume. Differences between the VEGF-NP group and all other groups were even greater when only small-sized vessels under 300 mum diameter were analyzed. In conclusion, sustained VEGF delivery via PLGA NPs shows promise for encouraging blood vessel growth in tissue engineering and cardiovascular medicine applications.
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19 MeSH Terms
Behavioral analysis of Ste20 kinase SPAK knockout mice.
Geng Y, Byun N, Delpire E
(2010) Behav Brain Res 208: 377-82
MeSH Terms: Acoustic Stimulation, Adaptation, Physiological, Animals, Behavior, Animal, Exploratory Behavior, Functional Laterality, Hindlimb Suspension, Hyperalgesia, Mice, Mice, Knockout, Muscle Strength, Pain Measurement, Pain Threshold, Phenotype, Protein-Serine-Threonine Kinases, Psychomotor Performance, Reflex, Startle, Statistics, Nonparametric, Swimming
Show Abstract · Added November 25, 2014
SPAK/STK39 is a mammalian protein kinase involved in the regulation of inorganic ion transport mechanisms known to modulate GABAergic neurotransmission in the both central and the peripheral nervous systems. We have previously shown that disruption of the gene encoding SPAK by homologous recombination in mouse embryonic stem cells results in viable mice that lack expression of the kinase. With the exception of reduced fertility, these mice do not exhibit an overt adverse phenotype. In the present study, we examine the neurological phenotype of these mice by subjecting them to an array of behavioral tests. We show that SPAK knockout mice displayed a higher nociceptive threshold than their wild-type counterparts on the hot plate and tail flick assays. SPAK knockout mice also exhibited a strong locomotor phenotype evidenced by significant deficits on the rotarod and decreased activity in open-field tests. In contrast, balance and proprioception was not affected. Finally, they demonstrated an increased anxiety-like phenotype, spending significantly longer periods of time in the dark area of the light/dark box and increased thigmotaxis in the open-field chamber. These results suggest that the kinase plays an important role in CNS function, consistent with SPAK regulating ion transport mechanisms directly involved in inhibitory neurotransmission.
Copyright 2009 Elsevier B.V. All rights reserved.
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19 MeSH Terms
Phosphocreatine recovery kinetics following low- and high-intensity exercise in human triceps surae and rat posterior hindlimb muscles.
Forbes SC, Paganini AT, Slade JM, Towse TF, Meyer RA
(2009) Am J Physiol Regul Integr Comp Physiol 296: R161-70
MeSH Terms: Adenosine Triphosphate, Adult, Animals, Electric Stimulation, Exercise, Female, Glycolysis, Hindlimb, Humans, Hydrogen-Ion Concentration, Kinetics, Least-Squares Analysis, Magnetic Resonance Spectroscopy, Male, Models, Biological, Muscle Contraction, Muscle Fibers, Skeletal, Muscle, Skeletal, Oxidative Phosphorylation, Phosphocreatine, Phosphorus Isotopes, Rats, Rats, Sprague-Dawley, Sciatic Nerve
Show Abstract · Added April 27, 2015
Previous studies have suggested the recovery of phosphocreatine (PCr) after exercise is at least second-order in some conditions. Possible explanations for higher-order PCr recovery kinetics include heterogeneity of oxidative capacity among skeletal muscle fibers and ATP production via glycolysis contributing to PCr resynthesis. Ten human subjects (28 +/- 3 yr; mean +/- SE) performed gated plantar flexion exercise bouts consisting of one contraction every 3 s for 90 s (low-intensity) and three contractions every 3 s for 30 s (high-intensity). In a parallel gated study, the sciatic nerve of 15 adult male Sprague-Dawley rats was electrically stimulated at 0.75 Hz for 5.7 min (low intensity) or 5 Hz for 2.1 min (high intensity) to produce isometric contractions of the posterior hindlimb muscles. [(31)P]-MRS was used to measure relative [PCr] changes, and nonnegative least-squares analysis was utilized to resolve the number and magnitude of exponential components of PCr recovery. Following low-intensity exercise, PCr recovered in a monoexponential pattern in humans, but a higher-order pattern was typically observed in rats. Following high-intensity exercise, higher-order PCr recovery kinetics were observed in both humans and rats with an initial fast component (tau < 15 s) resolved in the majority of humans (6/10) and rats (5/8). These findings suggest that heterogeneity of oxidative capacity among skeletal muscle fibers contributes to a higher-order pattern of PCr recovery in rat hindlimb muscles but not in human triceps surae muscles. In addition, the observation of a fast component following high-intensity exercise is consistent with the notion that glycolytic ATP production contributes to PCr resynthesis during the initial stage of recovery.
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24 MeSH Terms
The role of osteopontin in recovery from hind limb ischemia.
Duvall CL, Weiss D, Robinson ST, Alameddine FM, Guldberg RE, Taylor WR
(2008) Arterioscler Thromb Vasc Biol 28: 290-5
MeSH Terms: Animals, Endothelial Cells, Hindlimb, Ischemia, Lower Extremity, Macrophages, Male, Mice, Neovascularization, Physiologic, Osteopontin, Recovery of Function
Show Abstract · Added March 14, 2018
OBJECTIVE - Osteopontin (OPN) is a highly phosphorylated extracellular matrix glycoprotein that is involved in a diversity of biological processes. In the vascular wall, OPN is produced by monocytes/macrophages, endothelial cells, and smooth muscle cells, and it is thought to mediate adhesion, migration, and survival of these cell types. In this study, we hypothesized that OPN plays a critical role in recovery from limb ischemia.
METHODS AND RESULTS - We induced hind limb ischemia in wild-type and OPN-/- mice. OPN-/- mice exhibited significantly delayed recovery of ischemic foot perfusion as determined by LDPI, impaired collateral vessel formation as measured using micro-CT, and diminished functional capacity of the ischemic limb. In the aortic ring assay, normal endothelial cell sprouting was found in OPN-/- mice. However, OPN-/- peritoneal monocytes/macrophages were found to possess significantly reduced migration in response to chemoattraction.
CONCLUSIONS - This study provides evidence that a definitive biological role exists for OPN during ischemic limb revascularization, and we have suggested that this may be driven by impaired monocyte/macrophage migration in OPN-/- mice. These findings provide the first in vivo evidence that OPN may be a key regulator in postnatal vascular growth.
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11 MeSH Terms
CIB1 regulates endothelial cells and ischemia-induced pathological and adaptive angiogenesis.
Zayed MA, Yuan W, Leisner TM, Chalothorn D, McFadden AW, Schaller MD, Hartnett ME, Faber JE, Parise LV
(2007) Circ Res 101: 1185-93
MeSH Terms: Angiogenic Proteins, Animals, Calcium-Binding Proteins, Endothelial Cells, Hindlimb, Ischemia, Mice, Mice, Knockout, Neovascularization, Pathologic, Neovascularization, Physiologic, p21-Activated Kinases
Show Abstract · Added April 7, 2010
Pathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process on a molecular level. CIB1 (calcium- and integrin-binding protein), a 22-kDa EF-hand-containing protein, modulates the activity of p21-activated kinase 1 in fibroblasts. Because p21-activated kinase 1 also contributes to endothelial cell function, we hypothesized that CIB1 may have a role in angiogenesis. We found that endothelial cells depleted of CIB1 by either short hairpin RNA or homologous recombination have reduced migration, proliferation, and tubule formation. Moreover, loss of CIB1 in these cells decreases p21-activated kinase 1 activation, downstream extracellular signal-regulated kinase 1/2 activation, and matrix metalloproteinase 2 expression, all of which are known to contribute to angiogenesis. Consistent with these findings, tissues derived from CIB1-deficient (CIB1-/-) mice have reduced growth factor-induced microvessel sprouting in ex vivo organ cultures and in vivo Matrigel plugs. Furthermore, in response to ischemia, CIB1-/- mice demonstrate decreased pathological retinal and adaptive hindlimb angiogenesis. Ischemic CIB1-/- hindlimbs also demonstrate increased tissue damage and significantly reduced p21-activated kinase 1 activation. These data therefore reveal a critical role for CIB1 in ischemia-induced pathological and adaptive angiogenesis.
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Host immune competence and local ischemia affects the functionality of engineered vasculature.
Chen RR, Snow JK, Palmer JP, Lin AS, Duvall CL, Guldberg RE, Mooney DJ
(2007) Microcirculation 14: 77-88
MeSH Terms: Animals, Biocompatible Materials, Corrosion Casting, Drug Delivery Systems, Hindlimb, Immunocompetence, Ischemia, Laser-Doppler Flowmetry, Male, Mice, Mice, Inbred C57BL, Mice, SCID, Microspheres, Neovascularization, Physiologic, Polyglactin 910, Subcutaneous Tissue, Vascular Endothelial Growth Factor A
Show Abstract · Added March 14, 2018
OBJECTIVE - Localized and sustained delivery of vascular endothelial growth factor (VEGF) is a promising approach to overcome the limited efficacy of bolus delivery. The authors examined the effects of host immune competence and local ischemia on the functionality of new vessel networks formed with this approach.
METHODS - Vessel structure and perfusion resulting from implantation of porous 85:15 poly(lactide-co-glycolide) scaffolds releasing VEGF165 were measured in both subcutaneous tissue and ischemic hindlimbs of immune competent C57BL/6 and immune deficient SCID mice.
RESULTS - Sustained VEGF delivery resulted in a similar approximately 100% increase in vessel density within scaffolds in both implant sites, and both animal models. However, the resulting perfusion within scaffolds implanted in subcutaneous tissue increased modestly versus control (18-35%), while perfusion increased 52-110% above control when VEGF-releasing scaffolds were placed in ischemic hindlimbs of C57BL/6 or SCID mice. VEGF delivery improved perfusion in the entire ischemic limb (55 +/- 18% of the normal value by week 6; 138% increase over control) in SCID mice. Although C57BL/6 mice demonstrated spontaneous recovery from ischemia, VEGF delivery accelerated recovery as compared to control.
CONCLUSIONS - Localized and sustained VEGF delivery can create functional vasculature that amplifies recovery of tissue ischemia. However, increases in local and regional perfusion were highly dependent on the implantation site and the animal model.
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17 MeSH Terms
Comparison of a reference region model with direct measurement of an AIF in the analysis of DCE-MRI data.
Yankeelov TE, Cron GO, Addison CL, Wallace JC, Wilkins RC, Pappas BA, Santyr GE, Gore JC
(2007) Magn Reson Med 57: 353-61
MeSH Terms: Adenocarcinoma, Algorithms, Animals, Contrast Media, Gadolinium DTPA, Hindlimb, Image Processing, Computer-Assisted, Linear Models, Magnetic Resonance Imaging, Male, Models, Animal, Neoplasms, Experimental, Rats, Rats, Inbred F344
Show Abstract · Added December 10, 2013
Models have been developed for analyzing dynamic contrast-enhanced (DCE)-MRI data that do not require measurements of the arterial input function (AIF). In this study, experimental results obtained from a reference region (RR) analysis are compared with results of an AIF analysis in the same set of five animals (four imaged twice, yielding nine data sets), returning estimates of the volume transfer constant (Ktrans) and the extravascular extracellular volume fraction (ve). Student's t-test values for comparisons of Ktrans and ve between the two models were 0.14 (P=0.88) and 0.85 (P>0.4), respectively (where the high P-values indicate no significant difference between values derived from the two models). Linear regression analysis indicated there was a correlation between Ktrans extracted by the two methods: r2=0.80, P=0.001 (where the low P-value indicates a significant linear correlation). For ve there was no such correlation (r2=0.02). The mean (absolute) percent difference between the models was 22.0% for Ktrans and 28.1% for ve. However, the RR parameter values were much less precise than the AIF method. The mean SDs for Ktrans and ve for the RR analysis were 0.024 min-1 and 0.06, respectively, vs. 0.002 min-1 and 0.03 for AIF analysis.
Copyright (c) 2007 Wiley-Liss, Inc.
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14 MeSH Terms
Glucagon chronically impairs hepatic and muscle glucose disposal.
Chen SS, Zhang Y, Santomango TS, Williams PE, Lacy DB, McGuinness OP
(2007) Am J Physiol Endocrinol Metab 292: E928-35
MeSH Terms: Alanine, Animals, Blood Pressure, Dogs, Female, Glucagon, Glucose, Glycerol, Heart Rate, Hindlimb, Lactic Acid, Liver, Male, Muscle, Skeletal
Show Abstract · Added December 10, 2013
Defects in insulin secretion and/or action contribute to the hyperglycemia of stressed and diabetic patients, and we hypothesize that failure to suppress glucagon also plays a role. We examined the chronic impact of glucagon on glucose uptake in chronically catheterized conscious depancreatized dogs placed on 5 days of nutritional support (NS). For 3 days of NS, a variable intraportal infusion of insulin was given to maintain isoglycemia (approximately 120 mg/dl). On day 3 of NS, animals received a constant low infusion of insulin (0.4 mU.kg-1.min-1) and either no glucagon (CONT), basal glucagon (0.7 ng.kg-1.min-1; BasG), or elevated glucagon (2.4 ng.kg-1.min-1; HiG) for the remaining 2 days. Glucose in NS was varied to maintain isoglycemia. An additional group (HiG+I) received elevated insulin (1 mU.kg-1.min-1) to maintain glucose requirements in the presence of elevated glucagon. On day 5 of NS, hepatic substrate balance was assessed. Insulin and glucagon levels were 10+/-2, 9+/-1, 7+/-1, and 24+/-4 microU/ml, and 24+/-5, 39+/-3, 80+/-11, and 79+/-5 pg/ml, CONT, BasG, HiG, and HiG+I, respectively. Glucagon infusion decreased the glucose requirements (9.3+/-0.1, 4.6+/-1.2, 0.9+/-0.4, and 11.3+/-1.0 mg.kg-1.min-1). Glucose uptake by both hepatic (5.1+/-0.4, 1.7+/-0.9, -1.0+/-0.4, and 1.2+/-0.4 mg.kg-1.min-1) and nonhepatic (4.2+/-0.3, 2.9+/-0.7, 1.9+/-0.3, and 10.2+/-1.0 mg.kg-1.min-1) tissues decreased. Additional insulin augmented nonhepatic glucose uptake and only partially improved hepatic glucose uptake. Thus, glucagon impaired glucose uptake by hepatic and nonhepatic tissues. Compensatory hyperinsulinemia restored nonhepatic glucose uptake and partially corrected hepatic metabolism. Thus, persistent inappropriate secretion of glucagon likely contributes to the insulin resistance and glucose intolerance observed in obese and diabetic individuals.
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14 MeSH Terms