bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neovascularization and functional assessment of human pancreatic islets encapsulated with immuno‐modulatory stem cells
Authors: Azimi Mohammad Sadegh , He Yi , Wang Yong , Peirce‐Cottler Shayn , Pollok Brian 
Published: June 2021

Background & ObjectiveDeveloping successful therapies based on re‐introduction of healthy pancreatic islets in diabetic patients requires new strategies to combat the immune response caused by implantation, as well as improving neovascularization and engraftment of the implant. Human amniotic epithelial cells (AECs) are immuno‐modulatory stem cells that can confer a local immune‐privileged environment in vivo, and block grafted tissue rejection [1]. The objective of this study was to develop a protocol for encapsulating islets with AECs, and examine the effects of encapsulation on islet function, and neovascularization.MethodsHuman pancreatic islets were individually placed in ultra‐low attachment round bottom wells with human islet medium, and were divided into three experimental groups: 1) islet‐only, 2) adipose‐derived stem cells (ASCs)+islet, and 3) AECs+islet. For groups 2 and 3, each islet was assumed to have ~2000 beta cells, and the stem cells were added to each well to encapsulate individual islets at 2:1 cell ratio. The temporal c‐peptide secretion level was measured after 3 and 6 days by perfusing the islets with basal and high glucose solutions using dynamic readout assay, and confirmed the functionality of the encapsulated islets. To assess the angiogenic properties of encapsulation, cell culture supernates were collected after 6 days of culture, and used for an angiogenesis array kit, to identify and compare the level of 52 angiogenic factors present in each group. The same test was repeated for ASC‐ and AEC‐only cultures to identify any effects caused by the cell encapsulation.Results & ConclusionsThe level of pro‐angiogenic factors increased in encapsulated groups compared to the islet‐only group (Fig. 1). A larger increase in angiogenic factors in encapsulated islets compared to stem cell‐only groups demonstrated a synergetic angiogenic effect caused by encapsulation of islets with ASCs and AECs. To test the angiogenic response in a physiological scenario, the islets were seeded on rat mesentery tissues, and cultured for 6 days, and the level of angiogenic response was compared between different groups. Our results highlight the effect of encapsulating human islets with ASCs and AECs on engraftment and neovascularization, and showcase the potential of the islet cell encapsulation method for a successful long‐term implantation in patients with diabetes.Support or Funding InformationThe Virginia Catalyst and UVA Center for Advanced BiomanufacturingThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Interaction of obesity and Nrf2 deficiency exacerbates vascular aging: potential role of endothelial senescence
Authors: Balasubramanian Priya , Kiss Tamas , Tarantini Stefano , Yabluchanskiy Andriy , Csipo Tamas , Lipecz Agnes , Farkas Eszter , Ungvari Zoltan , Csiszar Anna 
Published: June 2021

Previous studies demonstrate that obesity promotes cognitive impairment due to, at least in part, its deleterious effects on the cerebral microvasculature. Importantly, the effects of obesity are exacerbated in aging, but the underlying mechanisms remain elusive. Nuclear factor erythroid 2‐related factor (Nrf2) is a master transcriptional factor that regulates the expression of anti‐oxidant and anti‐inflammatory genes. There is increasing evidence that Nrf2/ARE signaling plays a critical role in vascular resilience to obesity and the metabolic syndrome and that aging is associated with progressive Nrf2 dysfunction, promoting vascular oxidative stress. The present study was designed to test the hypothesis that Nrf2 deficiency exacerbates endothelial senescence and cerebromicrovascular dysfunction induced by obesity. To test this hypothesis, we developed a transgenic animal model to investigate senescence induced by Nrf2 deficiency by crossing Nrf2 knock out mice (Nrf2−/−) with a senescence reporter mice. In the senescence reporter mice, p16‐positive senescent cells can be detected in tissues by red fluorescent protein (mRFP) expression. Nrf2+/+ and Nrf2−/− senescence reporter mice were fed a standard diet or an adipogenic high fat diet (HFD) for 5 months. At the end of the dietary treatment, blood‐brain barrier (BBB) integrity was assessed by the permeability of the fluorescent tracer, Cadaverine Alexa‐fluor‐555 (Cad‐555) into the brain parenchyma. Endothelium‐dependent increases in cerebral blood flow (CBF) in response to contralateral whisker stimulation were measured by laser speckle contrast imaging. Finally, we assessed senescence in the hippocampus and cortex by quantifying mRFP positive endothelial cells and through gene expression analysis related to senescence pathways. HFD treatment in Nrf2+/+ mice for 6 months significantly increased the accumulation of Cad‐555 in the brain parenchyma, suggesting impaired BBB integrity. In addition, HFD treatment impaired endothelial function and significantly increased the expression of senescence related genes and number of RFP positive cells in the hippocampus of Nrf2+/+ animals. Nrf2 deficiency significantly exacerbated HFD‐induced BBB damage, endothelial senescence and worsened endothelial dysfunction, mimicking the aging phenotype. Together, these results provide additional evidence that intact Nrf2 signaling importantly contributes to cerebromicrovascular health, protecting against endothelial senescence and preserving endothelium‐dependent regulation of blood flow.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Targeting Plasminogen Activator Inhibitor‐1 Alleviates Inflammatory Responses Invoked by Sepsis or Chlorinated Lipid
Authors: Yu Hong , Wang Meifang , Wang Derek Z. , Kalogeris Theodore J. , Restrepo Ricardo J. , Fay William P. , Ford David A. , Korthuis Ronald J. 
Published: June 2021

Plasminogen activator inhibitor‐1 (PAI‐1) promotes leukocyte‐endothelium interactions and transmigration secondary to ischemia/reperfusion (I/R). Our previous work demonstrated that 2‐chlorohexadecanal (2‐ClHDA), derived from myeloperoxidase (MPO) produced hypochlorous acid (HOCL) targeting of plasmalogen phospholipids, may serve as a mediator of the inflammatory responses to sepsis. Given the fact that the septic inflammatory responses invoked by cecal ligation and puncture (CLP) can be reversed by an MPO inhibitor, we have postulated that sepsis‐induced inflammation may be mediated through MPO/HOCL/2‐ClHDA axis. However, the utility of drug targeting of PAI‐1 to inhibit inflammatory responses induced by CLP or 2‐ClHDA superfusion remains to be evaluated. We have begun to explore this issue by pretreating rats with PAI‐1 inhibitor, PAI‐039 (tiplaxtinin, 44 ug/kg) one hour prior to CLP or Sham surgery and then again one hour before beginning to take measurements. Six hours after surgery, inflammatory responses in four groups of Sprague‐Dawley rats (n=6) were quantified and compared on leukocyte‐endothelial cell interactions and mast cell degranulation in rat mesenteries using intravital microscopy. In other groups of rats pretreated with PAI‐039 one hour beforehand, the exposed mesenteries were superfused with 2‐ClHDA at 10 mM (a dose within the range of plasma concentrations reported for septic patients or rats) for ninety minutes, with inflammatory responses recorded at baseline, thirty, sixty and ninety minutes. The data showed that CLP or mesenteric superfusion with 2‐ClHDA induced marked increases in the numbers of rolling and firmly adherent leukocytes, and significant mast cell activation that were similar in magnitude in both models, and were prevented by pretreatment with the PAI‐1 inhibitor PAI‐039. Our results indicate that the increases in leukocyte rolling, leukocyte adhesion, and mast cell degranulation invoked by 2‐ClHDA superfusion mimicked the responses to CLP. Moreover, these proinflammatory responses appear to be dependent on PAI‐1.Support or Funding InformationSupported by NIH grant GM‐115553.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Vascular Dysfunction in Chronic Obstructive Pulmonary Disease (COPD): The Role of Mitochondrial‐derived Oxidative Stress
Authors: Kwon Oh Sung , Layec Gwenael , Broxterman Ryan M , Gifford Jayson R , Park Soung Hun , Shields Katherine L , Richardson Russell S 
Published: June 2021

BackgroundThis study sought to determine the contribution of mitochondrial‐derived oxidative stress in the vascular dysfunction exhibited by patients with COPD.MethodsVascular function was assessed with brachial artery flow‐mediated vasodilation (FMD) and the hyperemic response to both single and continuous passive leg movement (PLM) in 10 patients with COPD (55–70 years) before and after both the acute and chronic ingestion (4 weeks) of a mitochondrial‐targeted antioxidant (MitoQ) (20mg/day).ResultsBaseline % FMD (2.5 ± 0.9 %) in the patients with COPD was significantly enhanced by both the acute (3.3 ± 0.8 %) and 4 week (5.3 ± 1.2 %) MitoQ consumption. Acute MitoQ had no effect on the single PLM‐induced change in peak LBF (ΔPeak) or the area under the leg blood flow (LBF) response curve (AUC), but the 4 week MitoQ consumption significantly augmented both the single PLM ΔPeak (190±184 vs. 300±96 ml/min) and LBF AUC (20±14 vs. 50±16 ml). Compared to baseline (ΔPeak = 300±84 ml/min; LBF AUC = 80±34 ml), both ΔPeak and LBF AUC during continuous PLM‐were significantly enhanced with both the acute (ΔPeak: 435±96 ml/min; LBF AUC: 105±56 ml) and 4 week (ΔPeak: 622±106 ml/min; LBF AUC: 300±120 ml) MitoQ consumption.ConclusionsThis study reveals that, in patients with COPD, mitochondrial‐derived oxidative stress contributes significantly to the vascular dysfunction exhibited by this population. Therefore, targeting mitochondrial‐derived oxidative stress may, through an improvement in vascular function, be an efficacious approach to combat cardiovascular disease in patients with COPD.Support or Funding InformationThis work was funded, in part, by the National Heart, Lung, and Blood Institute at the National Institute of Health (PO1 HL1091830, K99HL 125756 and T32 HL139451), the Flight Attendant Medical Research Institute (FAMRI), and the Veteran's Administration Rehabilitation Research and Development Service (E6910‐R, E1697‐R, E1433‐P, E9275‐L and E1572‐P).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Xanthine Oxidase Mediates Cerebrovascular Function Impairment in Chronically Stressed Mice
Authors: Burrage Emily Nicole , Marshall Kent L. , Parsley Matthew C. , Tice Abigail L. , Aboaziza Eiman A. , Clay Allison , Frisbee Jefferson C , Kelley Eric E. , Chantler Paul D 
Published: June 2021

Chronic stress‐induced depression is a major cerebrovascular risk factor, and the link between obesity and depression is strong. We have previously shown that chronic stress in obese rats significantly reduces cerebrovascular function, mediated by an increase in oxidative stress. Xanthine oxidase (XO) is a major source of oxidative stress, thus, we examined the effects of Febuxostat (XO inhibitor) on improving cerebrovascular function after the development of depressive like symptoms.Diet induced obesity (60 kcal% fat) started at 6 weeks of age in C57BL/6 mice (n=12) lasting for a total of twenty weeks. During the final eight weeks, 6 mice underwent the unpredictable chronic mild stress (UCMS; 5 days/week for 7 Hrs/day) model to elicit a depressive phenotype. On week twenty, the mice were euthanized and the middle cerebral arteries (MCA) were removed and positioned in a pressurize myobath. To test for vessel health, the MCA was exposed it to increasing concentrations of acetylcholine (Ach; 10−9M to 10−4M) in the presence or absence of Febuxostat (40μM), XO (40μM), and L‐NAME (10−4M).MCA dilation to Ach was impaired in obese mice that underwent UCMS compared to obese control mice (7±1% vs. 23±3%, p<0.05). Incubating the MCA with Febuxostat for 30 minutes in the chamber did not improve MCA dilation to Ach in the obese control mice but restored MCA dilation in the UCMS obese mice (26±2% vs. 25±3%, p<0.05, respectively). Incubating the MCA with XO or L‐NAME had the same affect and reduced MCA dilation to Ach to 6% and 5%, respectively, in the obese control mice. Further, in the UCMS obese mice, max Ach dilation did not differ to the Ach dilation in the presence of L‐NAME. These data suggest that a depressive phenotype generates an increased production of reactive oxygen species possibly via increased activity of xanthine oxidase.Support or Funding InformationNIH Cobra Grant 5P20GM109098This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Dynamic cerebral carbon dioxide reactivity at rest and during exercise
Authors: Ogoh Shigehiko , Shigeki Shibata , Nakahara Hidehiro , Miyamoto Tadayoshi 
Published: June 2021

The cerebral vasculature is highly sensitive to direct arterial carbon dioxide tension (PaCO2) changes. Hypocapnia causes cerebral vasoconstriction, while hypercapnia causes cerebral vasodilation to maintain the brain tissue PCO2 within narrow limits. The cerebral blood flow (CBF) responses to PaCO2 changes should be quick, but the cerebral vasculature sensitivity as cerebral CO2 is measured during steady‐state vascular responses. Therefore, the CBF time response to PaCO2 changes remains unknown. The purpose of this study was to examine dynamic cerebral CO2 reactivity at rest and during exercise using the frequency domain analysis.Seven healthy young subjects participated in the study. At rest and during exercise (30% VO2max and cycling exercise), the dynamic CO2 reactivity was calculated based on the transfer function analysis between the end‐tidal CO2 (PETCO2) and the middle cerebral artery mean blood velocity (MCAvm), using a binary white‐noise sequence (0%–7% inspired CO2 fraction). Dynamic characteristics of the respiratory controller showed a low‐pass filter characteristic for regulating ventilation, and the dynamic gain was decreased gradually to 0.7 at 0.02 Hz. However, the gain from PETCO2 to MCAvm (dynamic CO2 reactivity) remained reasonably constant up to 0.02 Hz. Moreover, it did not change during exercise.These findings suggest that the dynamic cerebral CO2 reactivity is reflected in slow to fast PaCO2 changes, and does not change during exercise. In terms of CO2 homeostasis, the cerebral CO2 reactivity may be a more important physiological mechanism to adapt to fast CO2 changes than the ventilatory response to PaCO2 changes.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Examination of hemodynamic environments of carotid stenosis with computational fluid dynamics
Authors: Fukuda Shunichi , Shimogonya Yuji 
Published: June 2021

IntroductionCarotid arterial geometry is an independent risk factor for carotid stenosis, in which hemodynamics, classically low oscillatory shear stress, is thought to be involved. However, there are few reports indicating quantitative analyses of hemodynamic environments in carotid stenosis. Thus, we are conducting a prospective clinical study with computational fluid dynamic techniques, and 454 cases of carotid stenosis have been registered to date. Here, we focused on unilateral stenotic cases among them and compared hemodynamic distributions between stenotic and non‐stenotic sides. We also examined hemodynamic distributions of carotid arteries after releasing stenosis by carotid endarterectomy.MethodsHemodynamic distributions were examined using ANSYS‐CFX software. Patient‐specific arterial geometries and inflow velocities were obtained from 3‐dimensional computed tomographic angiography and carotid ultrasound Doppler examinations, respectively.ResultsIn both the stenotic area and the area proximal to the stenotic area, hemodynamic metrics indicating the magnitude of time‐averaged wall shear stress (TAWSS) were significantly higher compared with the non‐stenotic side (p=0.0027 and 0.0007, rspectively), whereas WSS disturbance‐based metrics, i.e. oscillating shear index (OSI, p=0.0006 and 0.0008) and normalized transverse WSS (NtransWSS, p<0.0001 and p=0.0029), were rather lower. However, in the region distal to the stenotic area, OSI (p=0.0009) and NtransWSS (p=0.0021), but not TAWSS (p=0.4564), were significantly higher as compared with the same area of non‐stenotic side (Figure). WSS gradient on carotid bulb after carotid endarterectomy was significantly higher compared with controls (p=0.037), suggesting that the carotid arteries may primarily have geometric risks for stronger hemodynamic stress.ConclusionsThe results suggested that hemodynamic environments in carotid stenosis are more complex than previously thought. High WSS in the stenotic area and enhanced WSS disturbance downstream of the stenotic area may be associated with progression of stenosis and plaque rupture.Support or Funding InformationThis study is supported by the Grant‐in‐Aid for the Japanese National Hospital Organization Multi‐Center Clinical Research, AMED under Grant Number JP15gm0810006h0301, and JSPS KAKENHI Grant Number 15K10323.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A novel role for the transplantation of adipose tissue in ischemia‐neovasculature
Authors: Wu Jianbo , Li Rong , Chen Liyuan , Wang Lin 
Published: June 2021

BackgroundFat deposition is associated with peripheral arterial disease. Adipose tissue has recently been implicated in vascular remodeling and angiogenic activity.We hypothesized that the transplantation of adipose tissues from normal mice improves blood flow perfusion and neovascularization in high‐fat diet fed mice.MethodsAfter 14 weeks of high‐fat diet (HFD)‐fed mice, unilateral hind limb ischemia was performed. Subcutaneous white adipose tissue (WAT) and brown adipose tissue (BAT) fat pads were harvested from normal EGFP mice, and subcutaneously transplanted over the region of the adductor muscles of HFD mice. Blood flow was measured using Laser Doppler Scanner. Vascular density, macrophages infiltration, and macrophage polarization were examined by RT‐qPCR, and immunohistochemistry.ResultsWe found that the transplantation of WAT derived from normal mice improved functional blood flow in HFD‐fed mice compared to mice transplanted with BAT and sham‐treated mice. WAT transplantation increased the recruitment of pericytes associated with nascent blood vessels, but did not affect capillary formation. Furthermore, transplantation of WAT prevented HFD‐induced insulin resistance, M2 macrophage predominance and the release of arteriogenic factors in ischemic muscles. Mice receiving WAT also displayed a marked reduction in several proinflammatory cytokines. In contrast, mice transplanted with BAT were glucose intolerant and demonstrated increased IL‐6 levels in ischemic muscles.ConclusionThese results indicate that transplantation of adipose tissue elicits improvements in blood perfusion and beneficial effects on systemic glucose homeostasis and could be a promising therapeutic option for the treatment of diabetic peripheral arterial disease.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China Grant (81172050, 81570263, and 81402431), Grant of Sichuan Province Science and Technology Agency Grant (2014FZ0104).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Extracellular matrix components isolated from diabetic mice alters cardiac fibroblast function through the AGE/RAGE signaling cascade
Authors: Burr Stephanie , Stewart James A 
Published: June 2021

Roughly 30 million Americans suffer from diabetes and these individuals are at an increased risk of developing cardiovascular complications. The most common type of cardiovascular complication is heart failure, where the heart is unable to adequately pump blood throughout the body. Heart failure can be a result of the stiffening of the left ventricle which occurs when cardiac fibroblasts become “active” and begin to remodel the extracellular matrix (ECM). Fibroblast “activation” can be triggered by the AGE/RAGE signaling cascade. Advanced Glycated End products (AGEs) are produced and accumulate in the ECM overtime in a healthy individual, but under hyperglycemic conditions, this process is accelerated. We aim to investigate how the presence of AGEs in the either diabetic or non‐diabetic ECM can affect fibroblast ECM remodeling as well as determine the role of AGE/RAGE signaling during this process. In order to assess this question diabetic and non‐diabetic fibroblasts were embedded in 3D matrices composed of collagen isolated from either diabetic or non‐diabetic mice. Fibroblast function was assessed using gel contraction, migration, proliferation, and protein expression. The role of AGE/RAGE signaling during the 3D matrix experiment was determined by either activating the signaling pathway using AGE‐BSA or inhibiting specific signaling components through drug treatments. Non‐diabetic fibroblasts displayed similar gel contraction to diabetic cells when embedded in diabetic collagen. Thus, suggesting the diabetic ECM can alter fibroblast function from “inactive” to “active” states. In addition, increasing the AGE/RAGE cascade leads to increase gel contraction whereas inhibiting the cascade leads to little or no gel contraction. These results indicate 1) the ECM from diabetic and non‐diabetic mice differ from one another, 2) diabetic ECM can impact fibroblast function and shift them towards an “active” state, and 3) that fibroblasts can modify the ECM through activation of the AGE/RAGE signaling cascade. These results suggest the importance of understanding the impact diabetes has on the ECM and fibroblast function, more specially how these two components are intertwined with one another. Unraveling this issue will provide better insight into the impact of diabetic and cardiovascular complications.Support or Funding InformationUS Army Medical Research Award #81XWH‐16‐1‐0710University of Mississippi School of Pharmacy; Department of BioMolecular SciencesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.